JP2016518438A - Combination of DPP-4 inhibitor and α-glucosidase inhibitor - Google Patents

Combination of DPP-4 inhibitor and α-glucosidase inhibitor Download PDF

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JP2016518438A
JP2016518438A JP2016513398A JP2016513398A JP2016518438A JP 2016518438 A JP2016518438 A JP 2016518438A JP 2016513398 A JP2016513398 A JP 2016513398A JP 2016513398 A JP2016513398 A JP 2016513398A JP 2016518438 A JP2016518438 A JP 2016518438A
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JP2016518438A5 (en
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トーマス クライン
トーマス クライン
マルク ミヒャエル
ミヒャエル マルク
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ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング
ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング
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Priority to PCT/EP2014/060160 priority patent/WO2014184376A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • A61K31/522Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/133Amines having hydroxy groups, e.g. sphingosine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The present invention relates to the use of certain DPP-4 inhibitors in combination with α-glucosidase inhibitors.

Description

  The present invention is preferably obese or overweight in patients in need thereof, for example in diabetic patients (which may have or may be at risk for small or large vessel disease or complications). Have or are at risk and / or have liver function or renal dysfunction (eg, those of mild, moderate, severe or ESRD stage) or at risk and / or used In a type 2 diabetic patient who may have shown / recommended a dose reduction of an α-glucosidase inhibitor (eg, in an elderly subject and / or in a subject with renal dysfunction, for example) For use in therapy, eg metabolic diseases, in particular diabetes, especially type 2 diabetes [eg postprandial hyperglycemia and / or In treating and / or preventing conditions related thereto (eg, including diabetic complications such as microvascular or macrovascular disease such as cardiovascular or cerebrovascular disease, nephropathy, retinopathy or neuropathy) and / or Or certain types of uses for improving weight control, reducing weight, inducing satiety, inhibiting gastric emptying, and / or reducing food intake A combination of a DPP-4 inhibitor (preferably linagliptin) and an α-glucosidase inhibitor (eg, a low dose form such as voglibose, miglitol or acarbose, preferably voglibose), wherein the α-glucosidase inhibitor / blocker is When co-administered with a DPP-4 inhibitor (preferably linagliptin) Reduced doses and / or infrequent (daily) administration (eg once, twice or three times a low dose of voglibose such as 0.2-0.3 mg; once a day twice Or 3 times low dose acarbose, such as 25-50 mg (or up to 100 mg); or low dose miglitol, such as once, twice or three times, 25-50 mg (or up to 100 mg)) It relates to a combination that may be present or used.

  The present invention further provides certain DPP-4 inhibitors [eg, GLP-1 receptor agonists (especially short-acting GLP-1), particularly for altering and / or reducing food intake by a subject. One or more other active agents, including GLP-1 mimetics, or GLP-1 analogs such as exenatide or native GLP-1 and / or α-glucosidase inhibitors (eg, low dose forms of voglibose , Miglitol or acarbose, preferably voglibose, preferably linagliptin], especially where the food is rich in fat and / or carbohydrates (eg high-calorie, palatable, sweet , And / or fatty foods), eg high glycemic index and / or monosaccharides and Beauty / or amount of disaccharide occupies a large part of the total carbohydrate content, and / or most of the total amount of energy is a food derived from adipose, to the use.

  Currently, lifestyles in many parts of the world are associated with or associated with numerous temptations of “lipid-producing”, sedentary, and caloric-rich environments, numerous diets, and caloric “ Characterized by “between meals” intake (eg, by solid food, snacks, and beverages) and lack of exercise.

  This lifestyle is often referred to as the “Western lifestyle” and is generally considered unhealthy. Our food previously consisted of an average of 10% protein, 30% fat and 60% carbohydrates, most of which were slowly absorbed forms of carbohydrates. Currently consumed foods, especially snacks between meals, have much higher amounts of rapidly absorbed carbohydrates and fats. The amount of rapidly absorbed hydrocarbon can be measured as a glycemic index or as a percentage of monosaccharides and disaccharides of the total carbohydrate content. Overdose of rapidly absorbed carbohydrates and / or high fat results in reduced hunger and increased stress. Some humans also have a craving for sweet and / or fatty foods, which may be increased by stress or premenstrual tension, or they appear psychologically as a distraction or obsessive eating habit May have other problems.

  As a result of this Western lifestyle, eating behavior, food or taste preferences, and / or psychological disorders as described above, food, particularly high-calorie unhealthy foods such as soda, juice, chocolate milk, sweetened coffee There is a common overdose of candy, chocolate, cakes, biscuits, crackers, French fries, burgers, jams or jellies or honeyed white bread, chips, sweet and fatty cereals.

Thus, in addition to or instead of traditional weight management algorithms such as diet, exercise, behavior or lifestyle modifications, or bariatric surgery (weight loss) surgery, especially in the case of extremely fat subjects, To control weight, to promote weight loss, for example to manage, treat or prevent weight gain, overweight, obesity, or other (metabolic) diseases or disorders related or related thereto, Healthy eating to change eating behavior, to adjust food or taste preferences, and / or to meet, for example, an individual's established nutritional requirements and a healthy nutritional lifestyle For weight management with pharmacological or pharmacotherapeutic interventions to maintain or adjust an appropriate balance between unhealthy eating and unhealthy eating The need for choices made still exists.
In the treatment of type 2 diabetes, α-glucosidase inhibitors (AGI; including acarbose, miglitol, voglibose) are recommended by the guidelines for glucose control in type 2 diabetes. AGI is effective in slowing the absorption of carbohydrates by the gastrointestinal tract by inhibiting α-glucosidase in the small intestine and thus lowering postprandial blood glucose and insulin levels.

  The present invention relates to patients in need thereof (for example diabetic patients who may or may not be obese, such as having or at risk for renal dysfunction, for example alpha-glucosidase inhibitors / blockers used. In diabetics) and / or in diabetics with or at risk for small or large vessel disease or complications) in combination with one or more other active agents Treatments (e.g. to improve blood sugar and / or weight control, to reduce weight, to induce satiety, to suppress gastric emptying, and / or to reduce food intake, and / Or metabolic disorders, especially diabetes, especially type 2 diabetes and / or conditions related thereto, eg small or large vessel diseases, eg Certain DPP-4 inhibitors (preferably linagliptin) for use in treating and / or preventing diabetic complications such as cardiovascular or cerebrovascular disease, nephropathy, retinopathy or neuropathy In combination with an α-glucosidase inhibitor / blocker (eg, voglibose, miglitol or acarbose, preferably voglibose), for example, the α-glucosidase inhibitor / blocker is combined with a DPP-4 inhibitor (preferably linagliptin) When co-administered, reduced doses and / or infrequent (daily) administration (eg, 1-3 times daily, low dose voglibose such as 0.2 mg; 1-3 times daily, 25-25 Low dose acarbose, such as 50 mg (or up to 100 mg); or 25 to 50 mg (or 10 times a day 1 to 3 times) Either present in mg up) low dose miglitol like), or relates to the combination used.

  In addition, the present invention provides side effects associated with therapeutic use of α-glucosidase inhibitors / blockers (eg, voglibose, miglitol, or acarbose), such as gastrointestinal adverse effects (eg, dyspepsia, hunger or diarrhea, or nausea or vomiting Certain DPP-4 inhibitors (one or more) for use in preventing, protecting from, reducing (eg, reducing the likelihood or occurrence of) Linagliptin), which may be used in combination with an active agent.

Thus, in certain specific embodiments, the present invention provides certain DPP-4 inhibitors (preferably linagliptin) and α-glucosidase inhibitors (eg, low dose forms such as voglibose, miglitol or acarbose, preferably Voglibose), or a combination or combination administration (eg, simultaneously, sequentially or separately).
The present invention further provides certain DPP-4 inhibitors [eg, GLP-1 receptor agonists (especially short acting GLP-1), particularly for altering and / or reducing food intake by a subject. One or more other active agents, and / or α-glucosidase inhibitors (eg, in low dose forms), including GLP-1 mimics, or GLP-1 analogs such as exenatide or native GLP-1 Linagliptin, which may be used in combination with voglibose, miglitol or acarbose, preferably voglibose), particularly where the food is rich in fat and / or carbohydrate (eg high calorie, palatable) Sweet and / or fatty foods), eg high glycemic index and / or monosaccharides The amount of pre / or disaccharide occupies a large part of the total carbohydrate content, and / or most of the total amount of energy is a food derived from adipose, to the use.

  Furthermore, the present invention relates to certain DPP-4 inhibitors (eg, one or more other active agents such as the GLP-1 receptor for appetite suppression, changes in food preferences, and / or weight loss). Agonists, such as short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs, such as exenatide or native GLP-1, and / or alpha-glucosidase inhibitors, such as voglibose, for example for weight control A combination of weight management and pre-diabetes / diabetes management in eg obese (eg human) subjects (eg glycemic control, eg appetite suppression), eg by using linagliptin , For food preference changes, weight loss, and / or weight control).

  The present invention further provides for reducing the intake of high calorie (mouthful, fat and / or carbohydrate rich) food and / or particularly unhealthy and / or high calorie (eg mouthful, fat And, in some cases, reducing the intake of healthy and / or low calorie food (eg relative to the intake of unhealthy and / or high calorie food) Certain DPP-4 inhibitions to regulate or change food or taste preferences, or food choices from intake of high calorie (mouthful, fat and / or carbohydrate rich) foods while increasing Drugs [eg GLP-1 receptor agonists (especially short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogs, such as Or in combination with one or more other active agents, including xenatide or natural GLP-1), and / or alpha-glucosidase inhibitors (eg, low dose forms of voglibose, miglitol or acarbose, preferably voglibose) Good, preferably linagliptin].

Accordingly, the present invention provides certain DPP-4 inhibitors [eg GLP-1 receptor agonists (especially short-acting effects) to change eating attitudes and change food and / or taste preferences to healthy foods. One or more other active agents and / or α-glucosidase inhibitors (eg, type GLP-1, GLP-1 mimetics, or GLP-1 analogs such as exenatide or native GLP-1) Low dose form of voglibose, miglitol or acarbose, preferably voglibose), preferably linagliptin].
Thus, the present invention provides certain DPP-4 inhibitors [eg GLP-1 receptor agonists (especially short acting) to alter eating attitudes and change food and / or taste preferences from unhealthy foods. One or more other active agents and / or α-glucosidase inhibitors (eg, type GLP-1, GLP-1 mimetics, or GLP-1 analogs such as exenatide or native GLP-1) Low dose form of voglibose, miglitol or acarbose, preferably voglibose), preferably linagliptin].

Furthermore, the present invention reduces caloric intake, excessive dietary energy intake, body weight, total body fat mass, total body fat percentage, visceral fat and / or overeating, facilitates their decrease, or prevents their increase Certain DPP-4 inhibitors [eg GLP-1 receptor agonists (especially short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or native GLP-1) Of linagliptin, preferably in combination with one or more other active agents and / or α-glucosidase inhibitors (eg low dose form of voglibose, miglitol or acarbose, preferably voglibose) Regarding use.
In one embodiment, a subject described herein has an overweight, with or without comorbid risk factors such as, for example, diabetes, dyslipidemia, hypertension, and / or metabolic syndrome Or you are obese.

In particular, the subject described herein is an overweight or obese person, for example with or without diabetes.
In another embodiment, the subject described herein is a subject that consumes food abnormally or excessively.
In another embodiment, a subject described herein is a subject with diabetes (eg, type 1 or type 2 diabetes, or LADA, particularly type 2 diabetes), for example with or without obesity or overweight.
In particular, a subject in the present invention may be a human, eg, a human child, a human adolescent, or a human adult.
In one embodiment, the combination of certain DPP-4 inhibitors (preferably linagliptin) with α-glucosidase inhibitors / blockers (eg, voglibose, miglitol or acarbose, preferably voglibose) avoids a high carbohydrate diet It can be particularly useful for subjects who dislike it.

In one embodiment, the combination of a certain DPP-4 inhibitor (preferably linagliptin) with an α-glucosidase inhibitor / blocker (eg, voglibose, miglitol or acarbose, preferably voglibose) is an Asian population (eg, East Asia, South Asia, or Southeast Asia) and / or in following an oriental diet with higher carbohydrate content.
In one embodiment, the combination of a certain DPP-4 inhibitor (preferably linagliptin) with an α-glucosidase inhibitor / blocker (eg, voglibose, miglitol or acarbose, preferably voglibose) is an Asian population (eg, , East Asia, South Asia, or Southeast Asia) and / or to reduce, treat, prevent or manage the adverse effects (on metabolism) of unhealthy Western diets.

  In one embodiment, the combination of a certain DPP-4 inhibitor (preferably linagliptin) with an α-glucosidase inhibitor / blocker (eg, voglibose, miglitol or acarbose, preferably voglibose) is an Asian population (eg, In East Asia, South Asia, or Southeast Asia) and / or in treating diabetes and / or obesity / overweight (especially like “diabetes obesity”) and / or (unhealthy) eating behavior Changing or changing (unhealthy) food or taste preferences (to a healthy diet) and / or life of an individual's established nutritional requirements and healthy nutritional status, for example Maintain or adjust the right balance between healthy and unhealthy eating to meet your style It may be particularly useful in.

For example, unhealthy food in the sense of the present invention may be food from one or more of groups A) to D).
A) Glycemic index is over 60% B) Glycemic index is over 40% and more than 30% of the total energy is derived from fat C) The amount of monosaccharides and / or disaccharides is the total carbohydrate content D) The amount of monosaccharides and / or disaccharides occupying more than 25% accounts for more than 25% of the total carbohydrate content and more than 30% of the total energy is derived from fat

For example, a healthy food in the sense of the present invention may be food from one or more of groups E to H.
E) Glycemic index is less than 60%.
F) Glycemic index is less than 40% and less than 30% of the total energy is derived from fat G) The combined amount of monosaccharides and / or disaccharides accounts for less than 25% of the total carbohydrate content H) The amount of monosaccharides and / or disaccharides accounts for less than 25% of the total carbohydrate content and less than 30% of the total energy is derived from fat

Furthermore, the present invention is a use in the treatment and / or prevention of a metabolic disease as described herein (eg type 2 diabetes and / or obesity), wherein a patient in need thereof (eg overweight, obesity, And / or diabetic patients), especially caloric intake, excessive dietary energy intake, body weight, total body fat mass, total body fat percentage, visceral fat and / or overeating reduction, facilitation of reduction or prevention of further increase In the patient in need and / or food, especially fat and / or carbohydrate rich food (eg high calorie, mouthful, sweet and / or fatty food), eg high glycemic index and / or The amount of monosaccharides and / or disaccharides occupies the majority of the total carbohydrates and / or the majority of the total energy And / or a reduction in the intake of high-caloric (mouth-rich, fat and / or carbohydrate-rich) foods in patients in need of altered and / or reduced intake of foods derived from fat, and / or Or further adjustment or change of food or taste preferences, or food selection, from unhealthy foods (eg, those described herein) to healthy foods (eg, those described herein) Require a reduction in the intake of, for example, unhealthy and / or high calorie (rich in mouth, fat and / or carbohydrate) food and / or healthy and / or low calorie food DPP-4 inhibitors [eg GLP-1 receptor agonists (especially short for use) in patients in need of increased intake of One or more other active agents and / or alpha-glucosidase inhibitors, including interactive GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1) (E.g., linagliptin, which may be used in combination with a low dose form of voglibose, miglitol or acarbose, preferably voglibose).

Accordingly, in certain embodiments, a preferred DPP-4 inhibitor within the meaning of the present invention is linagliptin.
For use in therapy (treatment or prevention) as defined herein, including certain DPP-4 inhibitors (preferably linagliptin) and optionally together with one or more other active agents Also contemplated are pharmaceutical compositions or combinations of:

Furthermore, the present invention may be used in combination with one, two or more additional active agents as defined herein, respectively, for use in the therapeutic methods (treatment or prevention) described herein. Species of DPP-4 inhibitors (preferably linagliptin).
Furthermore, the present invention is used in combination with one, two or more further active agents as defined herein, respectively, for preparing a pharmaceutical composition suitable for the therapeutic and / or prophylactic purposes of the present invention. Also relates to the use of certain DPP-4 inhibitors (preferably linagliptin).
Further, the present invention relates to a patient in need of an effective amount of certain DPP-4 inhibitors (preferably linagliptin), and optionally one or more other active or therapeutic agents, each as described herein. Relates to a therapeutic (treatment or prevention) method as described herein.

Other aspects of the invention will be apparent to those skilled in the art from the above and below (including examples and claims).
Aspects of the present invention, particularly pharmaceutical compounds, compositions, combinations, methods, and uses, include one or more other active agents as defined above and below, such as GLP-1 receptor agonists, particularly short acting. GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg low dose forms such as voglibose, miglitol or acarbose, preferably Refers to certain DPP-inhibitors (preferably linagliptin) that may be combined with voglibose).

2 is a graph showing that twice daily subcutaneous treatment of male Sprague Dawley rats (obesity model) with linagliptin and native GLP-1 results in significant body weight (BW) loss of up to 8%. Data represent the mean of 10 animals + SEM (standard error of the mean). 2 is a graph showing a significant reduction in body fat mass after application of a combination of linagliptin and natural GLP-1 in these animals. It is a graph showing that animals treated with linagliptin and native GLP-1 have a change in food preferences in reducing high fat diet intake. FIG. 4 is a graph showing that animals treated with linagliptin and native GLP-1 have a change in food preferences upon changing to a standard diet.

The glycemic index is an indicator of the ability of food to raise blood sugar levels. The glycemic index of food gives a group of at least 10 healthy humans a portion of food containing 50 grams of digestible (available) carbohydrate, and then to their blood glucose level for the next 2 hours Is determined by measuring the effect of. For each person, the area under the 2 hour glycemic response (glucose AUC) is measured. On another occasion, the same group of people takes 50 grams of glucose and their 2-hour glycemic response is also measured. The glycemic index of a food is the AUC determined for that food divided by the AUC measured for glucose and multiplied by 100% (calculated as the group average). Food with a high glycemic index contains carbohydrates that are rapidly digested, which causes a rapid rise and fall in the level of blood sugar. Conversely, foods with a low glycemic index score contain carbohydrates that are slowly digested, which causes a relatively gradual low rise in blood sugar levels.
In this context, monosaccharide is intended to indicate a carbohydrate that cannot be hydrolyzed to a simpler carbohydrate. The most important monosaccharides in food are glucose and fructose.

In this context, disaccharide is intended to denote a carbohydrate that can be hydrolyzed to two monosaccharides. The most important disaccharides in food are sucrose, maltose and lactose.
The amount of mono- or disaccharides in the food can be specifically analyzed by enzymatic, gas-liquid chromatography (GLC), or high performance liquid chromatography (HPLC) methods. Depending on the food matrix being analyzed, it may be desirable to extract low molecular weight carbohydrates in an aqueous ethanol solution (usually 80% (v / v)) prior to analysis. Related analytical methods include, for example, Southgate, "Determination of food carbohydrates", Elsevier, Science Publishers, Barkinggate, 1991; Greenfield, "Food composition data. Production, management and use", Elsevier Appleid Science, London, 1992; and Department of Health, "Dietery sugars and human health, Her Majesty's Stationary Office, London, 1989.

In this context, carbohydrates are "Carbohydrates in human nutrition. (FAO Food and Nutrition Paper-66)", Report of a Joint FAO / WHO Expert Consultation, Rome, 14-18 April 1997, Report of a Joint FAO / WHO Expert Consultation. Rome, 14-18 April 1997 can be defined as polyhydroxyaldehydes, ketones, alcohols, acids, simple derivatives thereof, and their polymers with acetal type linkages.
In this context, fat is intended to represent mono-, di-, and tricarboxylic esters derived from glycerol and cholesterol, of which glycerol is a more important energy source in food. The amount of fat in food can be determined as disclosed in FAO: Food energy-methods of analysis and conversion factors, Report of a Technical Workshop, Rome, 3-6 December 2002.
In this context, total carbohydrate content is intended to indicate the sum of carbohydrates present in food. Total carbohydrate content is not measured as such, but rather is calculated as the difference between the total mass of food and the sum of the masses of non-carbohydrate components (FAO: Food energy-methods of analysis and conversion factors, Report of a Technical Workshop, Rome, 3-6 December 2002).

In this context, food is intended to denote any form of food, ie both liquid and solid food, as well as basic food, and candy, snacks, etc. unless otherwise noted.
In this context, reducing food intake is by a group of one or more subjects who have been administered certain DPP-4 inhibitors that may be combined with another active agent, as shown in the present invention. Reduced amount of food eaten (measured by its energy content) compared to a similar control group not receiving certain DPP-4 inhibitors that may be combined with another active agent It is intended to show you what to do.

  Similarly, increasing food intake can be eaten by a group of one or more subjects who have been administered certain DPP-4 inhibitors that may be combined with another active agent, as shown in the present invention. The amount of food consumed (measured by its energy content) is increased compared to a similar control group that is not receiving certain DPP-4 inhibitors that may be combined with another active agent It is intended to show that.

In this context, an abnormal or excessive intake of food is an intake with pathological consequences such as obesity, or a psychological condition associated with, for example, pregnancy or premenstrual tension, or a distraction or compulsiveness It is intended to indicate intake that may result from psychological disorders such as eating habits.
As used herein, an effective amount of a compound cures, alleviates, or partially blocks a given condition or bodily abnormality, such as a disease or disorder, and signs of its complications (eg, clinical symptoms). Means enough. An amount effective to accomplish this is defined as an “effective amount”. Effective amounts for each purpose will depend on the condition, the severity of the disease or injury, and the weight and general state of the subject, form of administration, and the like. Determining the appropriate dosage is done using routine experiments that are within the ordinary skill of an experienced physician or veterinarian by building a matrix of values and testing different points in the matrix It will be understood that this is possible.

In this context, treating and treating means the management and care of a patient or subject for the purpose of combating a condition, such as a disease or disorder. The term is used to alleviate a symptom or complication, to slow the progression of a disease, disorder or condition, to alleviate or alleviate a symptom and complication, and / or to eliminate a disease, disorder or condition or It is intended to encompass the full range of treatment of a given condition that a patient or subject suffers, such as administration of an active compound, to cure as well as to prevent the condition, where prevention is a disease Should be understood as the management and care of a patient for the purpose of combating a condition, or disorder, including the administration of an active ingredient to prevent or delay the onset of symptoms or complications.
Unless otherwise noted, within the meaning of the invention, the use or method according to the invention is medical, eg therapeutic and / or prophylactic use / method, or non-medical, eg non-therapeutic. And / or any non-prophylactic use / method (eg, cosmetic use or method).

Thus, unless otherwise noted, within the meaning of the invention, treatment and / or prevention according to the invention is medical and / or preventive for therapeutic and / or prophylactic purposes, or It may relate either to treatment and / or prevention for non-medical, eg non-therapeutic and / or non-preventive purposes (eg cosmetic or lifestyle purposes).
Thus, in one aspect, the present invention provides a method for altering or reducing the intake of a particular type of food (eg, unhealthy food) by a subject (eg, an overweight, obese, and / or diabetic subject). Species or other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimics, or GLP-1 analogues such as exenatide or natural GLP-1, and / or Or the use of certain DPP-4 inhibitors (preferably linagliptin), which may be used in combination with an α-glucosidase inhibitor (for example in a low dose form such as voglibose, miglitol or acarbose, preferably voglibose), The food has a high glycemic index, and / or the monosaccharide and / or disaccharide The majority of the total carbohydrate content of the object, and / or most of the total energy is derived from fat in said food to provide a use.

In a further aspect, the invention provides a method for reducing food intake by a subject, wherein the food has a high glycemic index, wherein the method comprises one or more other active agents (eg, GLP- Effective doses of certain DPPs that may be used in combination with a single receptor agonist, in particular a short-acting GLP-1, GLP-1 mimetic, or GLP-1 analog such as exenatide or natural GLP-1) 4. A method is provided comprising administering to the subject a 4 inhibitor.
In particular in this embodiment, the glycemic index of the food may be greater than 60%, such as greater than 65%, such as greater than 70%, such as greater than 75%, such as greater than 80%, such as greater than 90%.

In a further aspect, the present invention is a method for reducing food intake by a subject, wherein monosaccharides and / or disaccharides comprise a majority of the total carbohydrate content of the food, Species or other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogues such as exenatide or natural GLP-1, and / or To said subject of an effective amount of certain DPP-4 inhibitors (preferably linagliptin), which may be used in combination with an alpha-glucosidase inhibitor (e.g. in a low dose form such as voglibose, miglitol or acarbose, preferably voglibose) A method comprising the administration of:
In particular in this embodiment, the amount of monosaccharides and / or disaccharides of the total carbohydrate content is more than 25%, such as more than 30%, such as more than 40%, such as more than 50%, such as more than 60%, such as 70%. It may be greater than%, such as greater than 80%, such as greater than 90%, or 100%.
In one embodiment of this aspect, the monosaccharide, disaccharide and trisaccharide together comprise more than 25% of the total carbohydrate content.

  In a further aspect, the present invention is a method for reducing food intake by a subject, wherein the food has a glycemic index greater than 40%, and greater than 30% of the total energy content is in the fat in the food. From which one or more other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogues such as exenatide or natural An effective amount of certain DPP-4 inhibitors (preferably, which may be used in combination with GLP-1 and / or an α-glucosidase inhibitor (eg, in a low dosage form such as voglibose, miglitol or acarbose, preferably voglibose) Provides linagliptin) to the subject.

In this embodiment, the glycemic index is greater than 40%, such as greater than 45%, such as greater than 50%, such as greater than 55%, such as greater than 60%, such as greater than 65%, such as greater than 70%, such as greater than 75%, such as greater than 80%. E.g. greater than 90% and greater than 30% of total energy, e.g. greater than 35%, e.g. greater than 40%, e.g. greater than 50%, e.g. greater than 60%, e.g. greater than 70%, e.g. greater than 80% Any combination of food is included.
In a further aspect, the present invention is a method for reducing food intake by a subject, wherein monosaccharides and / or disaccharides together comprise more than 25% of the total carbohydrate amount and 30% of the total energy amount. More than one of the fats in the food and the method is one or more other active agents (eg GLP-1 receptor agonists, especially short-acting GLP-1, GLP-1 mimics, or GLP- An effective amount of certain species that may be used in combination with one analog, such as exenatide or natural GLP-1, and / or an α-glucosidase inhibitor (eg, in a low dose form such as voglibose, miglitol or acarbose, preferably voglibose) Of administering a DPP-4 inhibitor (preferably linagliptin) to the subject.
In this embodiment, the monosaccharides and / or disaccharides together comprise more than 25% of the total carbohydrate amount, such as more than 30%, such as more than 40%, such as more than 45%, such as more than 50%, such as more than 70%, such as 80%. More than 90%, for example more than 90%, such as more than 30%, for example more than 35%, such as more than 40%, such as more than 50%, such as more than 60%, such as more than 70%, such as more than 80%. Any combination of foods that is derived from fat is included.

  Thus, in yet another aspect, the present invention is for altering or increasing the intake of a particular type of food (eg, healthy food) by a subject (eg, an overweight, obese, and / or diabetic subject). One or more other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogues such as exenatide or native GLP-1, and The use of certain DPP-4 inhibitors (preferably linagliptin) which may be used in combination with / or alpha-glucosidase inhibitors (for example in low dose form, such as voglibose, miglitol or acarbose, preferably voglibose) The food has a low glycemic index, and / or monosaccharides and / or disaccharides Serial occupies a small portion of the total carbohydrate content of food, and / or a small portion of the total energy is derived from fat in said food to provide a use.

In a further aspect, the invention relates to a method for increasing food intake by a subject, wherein the food has a low glycemic index, said method comprising one or more other active agents (eg GLP-1 receptor). Agonists, particularly short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg, low dose forms such as voglibose, A method is provided comprising administering to said subject an effective amount of certain DPP-4 inhibitors that may be used in combination with miglitol or acarbose, preferably voglibose).
In particular in this embodiment, the glycemic index of the food is less than 60%, such as less than 50%, such as less than 40%, such as less than 35%, such as less than 30%, such as less than 20%, such as less than 10%, such as less than 5%. May be.

  In a further aspect, the invention provides a method for increasing food intake by a subject, wherein monosaccharides and / or disaccharides comprise a small portion of the total carbohydrate content of the food, the method comprising one or more Other active agents (eg GLP-1 receptor agonists, especially short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogues such as exenatide or natural GLP-1 and / or α-glucosidase inhibition Administration to said subject of an effective amount of a certain DPP-4 inhibitor (preferably linagliptin), which may be combined with a drug (eg in a low dose form such as voglibose, miglitol or acarbose, preferably voglibose) Provide a way.

In particular in this embodiment, the amount of monosaccharides and / or disaccharides of the total carbohydrate content is less than 25%, such as less than 20%, such as less than 15%, such as less than 10%, such as less than 5%. May be.
In one embodiment of this aspect, the monosaccharide, disaccharide and trisaccharide together comprise less than 25% of the total carbohydrate content.
In a further aspect, the invention is a method for increasing food intake by a subject, wherein the food has a glycemic index of less than 40% and less than 30% of the total energy amount is derived from fat in the food. Wherein the method comprises one or more other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogues such as exenatide or natural GLP- 1 and / or an effective amount of a certain DPP-4 inhibitor (preferably linagliptin) that may be used in combination with an α-glucosidase inhibitor (eg in a low dose form, eg voglibose, miglitol or acarbose, preferably voglibose) ) Is administered to the subject.

In this embodiment, the glycemic index is less than 40%, such as less than 30%, such as less than 20%, such as less than 10%, such as less than 5%, and less than 30%, such as less than 20%, such as less than 10% of the total energy. Any combination of food is included, eg, less than 5% is derived from fat.
In a further aspect, the invention is a method for increasing food intake by a subject, wherein monosaccharides and / or disaccharides together comprise less than 25% of the total carbohydrate amount and 30% of the total energy amount. Less than derived from fat in the food and the method is one or more other active agents (eg GLP-1 receptor agonists, especially short-acting GLP-1, GLP-1 mimics, or GLP- An effective amount of certain species that may be used in combination with one analog, such as exenatide or natural GLP-1, and / or an α-glucosidase inhibitor (eg, in a low dosage form such as voglibose, miglitol or acarbose, preferably voglibose) Of administering a DPP-4 inhibitor (preferably linagliptin) to the subject.

In this embodiment, monosaccharides and / or disaccharides together comprise less than 25% of the total carbohydrate amount, such as less than 20%, such as less than 15%, such as less than 10%, such as less than 5%, and 30% of the total energy amount. Any combination of food that is less than, such as less than 25%, such as less than 20%, such as less than 15%, such as less than 10%, such as less than 5%, is derived from fat.
In another embodiment, a food with a high glycemic index as described above and / or a food in which monosaccharides and / or disaccharides make up the majority of the total carbohydrate content, and / or a majority of the total energy content is derived from fat. The reduction in food intake is a food with a low glycemic index as described above and / or a food in which monosaccharides and / or disaccharides make up a small portion of the total carbohydrate content and / or a small portion of the total energy content. With increased intake of foods that are derived from fat.

  Accordingly, in yet another aspect, the present invention relates to food or taste preferences, or food choices in a subject (eg, an overweight, obese, and / or diabetic subject), eg, as described above, if the glycemic index is Regulate from unhealthy foods that are high and / or monosaccharides and / or disaccharides make up the majority of the total carbohydrate content of the food and / or the majority of the total energy content is derived from fat in the food Or one or more other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimics, or GLP-1 analogues, such as exenatide or natural, for altering GLP-1 and / or α-glucosidase inhibitors (eg, low dose forms such as voglibose, mi Lithol or acarbose, preferably may be used in combination with voglibose), certain DPP-4 inhibitors (preferably provides the use of linagliptin).

  Accordingly, in yet another aspect, the present invention relates to food or taste preferences, or food choices in a subject (eg, an overweight, obese, and / or diabetic subject), eg, as described above, if the glycemic index is A low and / or monosaccharide and / or disaccharide makes up a small portion of the total carbohydrate content of the food and / or a small amount of the total energy amount is adjusted to a healthy food One or more other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimics, or GLP-1 analogues such as exenatide or Natural GLP-1)), and / or an α-glucosidase inhibitor (eg in a low dosage form, eg voglibose, Gulitol or acarbose, preferably may be used in combination with voglibose), certain DPP-4 inhibitors (preferably provides the use of linagliptin).

  Accordingly, in yet another aspect, the present invention provides a food or taste preference, or food choice, in a subject (eg, an overweight, obese, and / or diabetic subject), eg, a high glycemic index, and / or Glycemic index from unhealthy foods where monosaccharides and / or disaccharides occupy most of the total carbohydrate content and / or most of the total energy amount is derived from fat (each as described in more detail above) Low and / or monosaccharides and / or disaccharides occupy a small portion of the total carbohydrate content and / or a small portion of the total energy amount is derived from fat (each as described in more detail above) One or more other active agents (e.g. GLP-1 receptor agonists) to regulate or change into a healthy food In particular, short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg low dose forms such as voglibose, There is provided the use of certain DPP-4 inhibitors (preferably linagliptin) which may be used in combination with miglitol or acarbose, preferably voglibose.

  For example, in one embodiment, the invention provides a method for reducing food intake by a subject (eg, an overweight, obese, and / or diabetic subject), wherein the food has a glycemic index greater than 60%. Or the food has a glycemic index greater than 40%, combined with that more than 30% of the total energy is derived from fat, and the method comprises another active agent (eg, a GLP-1 receptor agonist, In particular short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg in low dose forms such as voglibose, miglitol or An effective amount of certain DPP-4 inhibitors (preferably ribo) that may be used in combination with acarbose, preferably voglibose. The Guripuchin) comprising administering to said subject, to a method.

  In another embodiment, the present invention provides a method for reducing food intake by a subject (eg, an overweight, obese, and / or diabetic subject) comprising said monosaccharide and / or disaccharide in said food. Sugars together account for more than 25% of the total carbohydrate content of the food, and the method is another active agent (eg GLP-1 receptor agonist, especially short-acting GLP-1, GLP-1 mimic, or GLP -1 analogues such as exenatide or natural GLP-1) and / or an α-glucosidase inhibitor (eg in a low dose form such as voglibose, miglitol or acarbose, preferably voglibose) It relates to a method comprising administering to the subject a certain DPP-4 inhibitor (preferably linagliptin).

In another embodiment, the invention provides a method for reducing food intake by a subject (eg, an overweight, obese, and / or diabetic subject) wherein more than 30% of the total energy is derived from fat The monosaccharides and / or disaccharides in the food together account for more than 25% of the total carbohydrate content of the food, and the method comprises another active agent (eg, a GLP-1 receptor agonist, In particular short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg in low dose forms such as voglibose, miglitol or An effective amount of certain DPP-4 inhibitors (preferably linagliptin) that may be used in combination with acarbose, preferably voglibose) Comprising administering to said subject, to a method.
In another embodiment, the invention is a method of increasing food intake in a subject, wherein the food has a glycemic index of less than 60%, or the food is less than 30% of the total amount of energy. Combined with being derived from fat and having a glycemic index of less than 40%, the method is another active agent (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimics, Or an effective amount that may be used in combination with a GLP-1 analog, such as exenatide or natural GLP-1, and / or an α-glucosidase inhibitor (eg, in a low dose form such as voglibose, miglitol or acarbose, preferably voglibose) Administering a certain DPP-4 inhibitor (preferably linagliptin) to said subject. About.

  In another embodiment, the invention provides a method for increasing food intake in a subject, wherein monosaccharides and / or disaccharides together comprise less than 25% of the total carbohydrate content of the food, Other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogues, eg exenatide or native GLP-1, and / or α-glucosidase inhibition Administering to said subject an effective amount of a certain DPP-4 inhibitor (preferably linagliptin), which may be combined with a drug (eg, in a low dosage form, such as voglibose, miglitol or acarbose, preferably voglibose). Including methods.

  In another embodiment, the present invention is a method for increasing food intake in a subject, wherein monosaccharides and / or disaccharides are combined with less than 30% of the total energy being derived from fat. Accounted for less than 25% of the total carbohydrate content of the food and the method is another active agent (eg GLP-1 receptor agonists, especially short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs) An effective amount of certain DPPs that may be used in combination with a body, such as exenatide or natural GLP-1, and / or an α-glucosidase inhibitor (eg, in a low dosage form such as voglibose, miglitol or acarbose, preferably voglibose) A method comprising administering to the subject a -4 inhibitor (preferably linagliptin).

  In another embodiment, the present invention is a method of treating a subject who has an abnormal or excessive intake of food, wherein the glycemic index is greater than 60%, or greater than 30% of the total energy is derived from fat. Together with a glycemic index greater than 40% and the method is a different active agent (eg a GLP-1 receptor agonist, in particular a short-acting GLP-1, GLP-1 mimetic, or GLP-1 analog) An effective amount of certain DPP-, which may be used in combination with e.g. exenatide or natural GLP-1 and / or an alpha-glucosidase inhibitor (e.g. in a low dose form such as voglibose, miglitol or acarbose, preferably voglibose) A method comprising administering to the subject a 4 inhibitor (preferably linagliptin).

In another embodiment, the present invention is a method of treating a subject who has an abnormal or excessive intake of food, wherein monosaccharides and / or disaccharides together comprise more than 25% of the total carbohydrate content, Other active agents (eg GLP-1 receptor agonists, in particular short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogues, eg exenatide or native GLP-1, and / or α-glucosidase inhibition Administering to said subject an effective amount of a certain DPP-4 inhibitor (preferably linagliptin), which may be combined with a drug (eg, in a low dosage form, such as voglibose, miglitol or acarbose, preferably voglibose). Including methods.
In another embodiment, the present invention is a method of treating a subject that has an abnormal or excessive intake of food, wherein more than 30% of the total amount of energy is derived from fat, in combination with monosaccharides and / or disaccharides. The saccharides together account for more than 25% of the total carbohydrate content and the method is another active agent such as a GLP-1 receptor agonist, particularly a short acting GLP-1, GLP-1 mimetic, or GLP-1 analog An effective amount of certain DPPs that may be used in combination with a body, such as exenatide or natural GLP-1, and / or an α-glucosidase inhibitor (eg, in a low dosage form such as voglibose, miglitol or acarbose, preferably voglibose) A method comprising administering to the subject a -4 inhibitor (preferably linagliptin).

  In another embodiment, the present invention provides a food or taste preference, or food selection, in a subject (eg, an overweight, obese, and / or diabetic subject) that has a glycemic index greater than 60% or total energy. A method of modulating or changing from a food having a glycemic index greater than 40% in combination with that more than 30% of the amount is derived from fat, comprising another active agent (e.g. GLP-1 receptor agonist, particularly short Time-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg, low dose forms such as voglibose, miglitol or acarbose, An effective amount of certain DPP-4 inhibitors (preferably, preferably in combination with voglibose) Comprises administering linagliptin) to the subject, to a method.

  In another embodiment, the present invention provides food or taste preferences, or food choices in a subject (eg, an overweight, obese, and / or diabetic subject) combined with monosaccharides and / or disaccharides to total carbohydrates. A method of modulating or changing from a food occupying more than 25% of the amount of another active agent (eg a GLP-1 receptor agonist, in particular a short-acting GLP-1, GLP-1 mimic, or GLP- An effective amount of certain species that may be used in combination with one analog, such as exenatide or natural GLP-1, and / or an α-glucosidase inhibitor (eg, in a low dosage form such as voglibose, miglitol or acarbose, preferably voglibose) A method comprising administering to said subject a DPP-4 inhibitor (preferably linagliptin) .

  In another embodiment, the present invention provides a food or taste preference, or food selection, in a subject (eg, an overweight, obese, and / or diabetic subject), wherein more than 30% of the total energy is derived from fat. And a method of modulating or altering from a food that monosaccharides and / or disaccharides together account for more than 25% of the total carbohydrate content, comprising another active agent (eg a GLP-1 receptor agonist, in particular Short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg, low dose forms such as voglibose, miglitol or acarbose) An effective amount of certain DPP-4 inhibitors (preferably libo), which may be used in combination with (preferably voglibose). The Guripuchin) comprising administering to said subject, to a method.

In another embodiment, the present invention provides a food or taste preference, or food selection in a subject (eg, an overweight, obese, and / or diabetic subject) that has a glycemic index of less than 60% or total energy. A method of adjusting or changing to a food having a glycemic index of less than 40% in combination with less than 30% of the amount being derived from fat, comprising another active agent (eg a GLP-1 receptor agonist, in particular Short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg, low dose forms such as voglibose, miglitol or acarbose) Effective amounts of certain DPP-4 inhibitors (preferably voglibose) Mashiku comprises administering linagliptin) to the subject, to a method.
In another embodiment, the present invention provides food or taste preferences, or food choices in a subject (eg, an overweight, obese, and / or diabetic subject) combined with monosaccharides and / or disaccharides to total carbohydrates. A method of modulating or changing to a food comprising less than 25% of the amount, comprising another active agent (eg GLP-1 receptor agonist, in particular a short-acting GLP-1, GLP-1 mimic, or GLP Effective amounts that may be used in combination with -1 analogs such as exenatide or natural GLP-1 and / or alpha-glucosidase inhibitors (eg, in low dose forms such as voglibose, miglitol or acarbose, preferably voglibose) To a method comprising administering a DPP-4 inhibitor (preferably linagliptin) to the subject. That.

  In another embodiment, the invention provides for a food or taste preference, or food selection in a subject (eg, an overweight, obese, and / or diabetic subject) that is less than 30% of the total amount of energy is derived from fat. And a method of modulating or changing monosaccharides and / or disaccharides to foods that together comprise less than 25% of the total carbohydrate content, comprising another active agent (eg, a GLP-1 receptor agonist, In particular short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1, and / or α-glucosidase inhibitors (eg in low dose forms such as voglibose, miglitol or An effective amount of certain DPP-4 inhibitors (preferably, which may be used in combination with acarbose, preferably voglibose) The linagliptin) comprising administering to said subject, to a method.

The amount of energy in food is generally indicated in calories or joules, which can be measured, for example, by burning food in a bomb calorimeter. The amount of energy due to fat can be determined by multiplying the amount of fat in the food analyzed as described above by 38 kJ / g.
It is well known that people prefer sweet and / or fatty foods because many people think that sweet and / or fatty foods have a good taste. Accordingly, the present invention is a method of adjusting taste preferences, particularly from sweet and fatty foods, in an effective amount that may be used in combination with one or more other active agents. Also provided is a method comprising administering a certain DPP-4 inhibitor, preferably linagliptin.

The unhealthy Western lifestyle is quite obvious, as evidenced by an increase in obesity with pathological consequences such as diabetes and diabetic complications. You must think that there is. Thus, in one embodiment, the present invention is a method of normalizing lifestyle, particularly food preferences, in an effective amount of certain DPP-s that may be used in combination with one or more other active agents. Also provided is a method comprising administering a 4 inhibitor, preferably linagliptin.
In one embodiment, the subject being treated has a strong appetite, hunger, or a craving for sweet or fatty food. This may be related to, for example, stress, smoking cessation, pregnancy, premenstrual tension, and may be due to physiological problems or diseases such as distraction eating, compulsive eating habits, and seasonal affective disorder There is also.

Distraction eating disorder (BED) is a fairly new diagnosable disorder (see, for example, Int. J. Obesity, 2002, 26, 299-307 and Curr. Opin. Pshyciatry, 17, 43-48, 2004). I want. BED, like bulimia nervosa (BN), is characterized by a distraction episode. However, subjects with BED, contrary to patients with BN, do not perform compensatory actions such as self-induced vomiting, excessive exercise, and laxative, diuretic or enema abuse. Studies have shown that 1-3% of the general population suffer from BED, whereas higher prevalence (up to 25-30%) has been reported for obese patients [Int. Obesity, 2002, 26, 299-307]. These numbers indicate that the subject of BED may or may not be obese, and that obese patients may or may not have BED, ie the cause of obesity is BED It is shown that. However, some subjects with BED eventually become obese due to excessive caloric intake. Laboratory studies have shown that BED patients consume more desserts and snacks (rich in fat and less protein) than obese controls [Int. J. Obesity, 2002, 26, 299-307], therefore, the methods of the invention are considered suitable for the treatment of BED.
In one embodiment, the present invention is a method of treating BED in a subject comprising an effective amount of certain DPP-4 inhibitors (preferably, which may be used in combination with one or more other active agents). Linagliptin) to the subject. In particular, the subject is obese.

  Bulimia nervosa (BN) is characterized by the same distraction episode as BED, but BN is also characterized by the above-mentioned compensatory behavior. Some subjects with BN eventually become obese to the extent that compensatory actions cannot fully compensate for excessive caloric intake. The study compared binges in BN patients with those in BED patients and concluded that overfood in subjects with BN had higher carbohydrate and sugar content than overfood in subjects with BED . However, there was no difference in the calorie intake [Int. J. Obesity, 2002, 26, 299-307]. Therefore, the method of the present invention is considered suitable for the treatment of BN.

In one embodiment, the present invention is a method of treating BN in a subject comprising an effective amount of certain DPP-4 inhibitors (preferably, which may be used in combination with one or more other active agents). Linagliptin) to the subject. In particular, the subject is obese.
A craving for food or a strong desire to eat certain foods is usually associated with high energy foods such as fatty or carbohydrate rich foods [Appetite, 17, 177-185, 1991; Appetite, 17, 167-175, 1991]. Examples of such foods include chocolate, biscuits, cakes and snacks. Some of those who want extraordinary food eventually become obese due to excessive caloric intake. The methods of the invention are believed to be suitable for the treatment of food cravings, particularly cravings for fatty or carbohydrate rich foods.

In one embodiment, the invention provides a method of treating a food craving, eg, a craving for a fatty or carbohydrate rich food, eg, a craving for chocolate, in a subject, comprising one or more other activities. An effective amount of a DPP-4 inhibitor (preferably linagliptin) that may be used in combination with the agent. In particular, the subject is obese.
Snacks are convenient, generally light, easy, and hurried foods that are eaten between meals. Snacks are generally high in fat and rich in carbohydrates. Studies show that snacking epidemics are growing, especially among US children, and snacking is a major cause of increased BMI, for example in children [J. Pediatrics, 138 , 493-498, 2001; Obes. Res., 11, 143-151, 2003]. Changes to healthier snacks may possibly stop or change the recent rise in BMI. The data presented here shows that certain DPP-4 inhibitors, which may be combined with one or more other active agents, can change food preferences, from fat rich carbohydrate rich foods to low fat glycemic index. It illustrates that it can be changed to low food. Accordingly, certain DPP-4 inhibitors, which may be used in combination with one or more other active agents, are useful in reducing the amount of snack or changing snack preferences to healthier snacks. .

In one embodiment, the present invention provides a method of changing a snack preference in a subject to a low fat, low glycemic index snack, which may be used in combination with one or more other active agents. It relates to a method comprising administering to the subject a certain DPP-4 inhibitor (preferably linagliptin). In particular, the subject is obese.
In one embodiment, the present invention is a method of reducing a subject's amount of snack consumption (“snack”), an effective amount of certain DPPs that may be combined with one or more other active agents. A method comprising administering a -4 inhibitor (preferably linagliptin) to said subject. In particular, the subject is obese.

In accordance with the foregoing discussion, one or more other active agents (eg, GLP-1 receptor agonists, particularly short-acting GLP-1, GLP-1 mimetics, or GLP-1 analogs such as exenatide or Certain DPP-4 inhibitors (preferably linagliptin) that may be used in combination with native GLP-1 and / or α-glucosidase inhibitors (eg, in low dose forms such as voglibose, miglitol or acarbose, preferably voglibose) ) Are considered useful in the treatment of obesity or overweight caused by BED, BN, food craving (eg, craving for chocolate), or snacking or overeating.
The subject of the invention can in principle be any animal, in particular mammals such as humans, pet animals such as cats and dogs, and zoo animals such as elephants, giraffes, lions and snakes, among which humans preferable.

  Type 2 diabetes generally results from a complex pathophysiological event involving the dual endocrine effects of insulin resistance and impaired insulin secretion, with the consequence of not meeting the requirements necessary for maintaining normal ranges of plasma glucose levels. Chronic and progressive diseases. This leads to chronic hyperglycemia and associated microvascular or macrovascular complications or chronic disorders such as diabetic nephropathy, retinopathy or neuropathy, or macrovascular (eg cardiovascular or cerebrovascular) complications. Vascular disease components play an important role in a range of diabetes-related diseases, but are not the only factors. Frequent complications lead to a significant reduction in life expectancy. Due to diabetes-induced complications, diabetes is currently the most common cause of blindness, renal failure and amputation in adults, two to five times the risk of cardiovascular disease in industrialized countries. Associated with a fold increase.

  In addition, diabetes (especially type 2 diabetes) exists with and often correlates with obesity, and these two conditions together pose particularly complex therapeutic challenges. Because of the effect of obesity on insulin resistance, weight loss and its maintenance is an important therapeutic goal for overweight or obese individuals with pre-diabetes, metabolic syndrome or diabetes. Studies have shown that weight loss in subjects with type 2 diabetes is associated with decreased insulin resistance, improved blood glucose or lipemia readings, and decreased blood pressure. Maintaining weight loss over time is thought to improve glycemic control and prevent diabetic complications (eg, reduced risk of cardiovascular disease or event). Weight loss is therefore recommended for all overweight or obese individuals who have or are at risk for diabetes. However, obese patients with type 2 diabetes suffer much more from losing weight and maintaining reduced weight than the general non-diabetic population.

In this context, obese or obesity means excess adipose tissue. In this context, obesity is best considered to be any degree of excessive steatosis that poses a health risk. The difference between normal and obese individuals can only be approximated, but the health risks posed by obesity are probably integral to the increased steatosis. In a broad sense, an individual whose body mass index (BMI = weight (kilogram) ÷ height (m) squared) exceeds 25 (or ≧ 30 kg / m 2 or ≧ 27 kg / m 2 ) is considered obese.
Overweight, individuals can be defined as a state having greater than 25kg / m 2 30kg / m 2 less than body mass index (BMI). The terms “overweight” and “pre-diabetes” are used interchangeably.
Obesity can also be defined as a condition in which an individual has a BMI of 30 kg / m 2 or greater. According to the definition of WHO, the term “obesity” can be classified as follows. Class I obesity is a condition with a BMI of 30 kg / m 2 or more but less than 35 kg / m 2 , and Class II obesity has a BMI of 35 kg / m 2 or more but less than 40 kg / m 2 A class III obesity (excessive obesity) is a condition in which the BMI is 40 kg / m 2 or more. Obesity can include, for example, visceral obesity and abdominal obesity.
Visceral obesity can be defined as a condition where the waist to hip ratio is measured as 1.0 or more for men and 0.8 or more for women. It indicates the risk of insulin resistance and the occurrence of prediabetes.

  Abdominal obesity can generally be defined as a condition where the waist circumference is greater than 40 inches or 102 cm for men and greater than 35 inches or 94 cm for women. For Japanese or Japanese patients, abdominal obesity is defined as 85 cm or more for men around the waist and 90 cm or more for women (for example, the investigating committee for the diagnosis of metabolic syndrome in Japan) Japan)).

Treatment of type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy. Conventional monotherapy can initially control blood glucose in some patients, but it is associated with a high secondary failure rate. The limitations of monotherapy for maintaining glycemic control are overcome by the combination of multiple drugs in at least some patients and for a limited period of time to achieve unsustainable glycemic reduction during long-term therapy with a single agent be able to. Available data support the conclusion that in most patients with type 2 diabetes, conventional monotherapy will fail and treatment with multiple drugs will be required.
However, because type 2 diabetes is a progressive disease, even patients with a good initial response to conventional combination therapy will eventually require increased dosage or further treatment with insulin . This is because it is very difficult to stably maintain the blood sugar level for a long period of time. Existing combination therapies have the potential to increase glycemic control but are not without limitations (especially with regard to long-term efficacy). In addition, previous therapies may exhibit an increased risk of side effects (eg, hypoglycemia or weight gain), which may impair the effectiveness and tolerability of previous therapies.

Thus, for many patients, these existing drug therapies result in progressive deterioration of metabolic control despite treatment, especially in the long term, where metabolic status cannot be adequately controlled and are therefore progressive Failure to achieve and maintain glycemic control in type 2, advanced, or late type 2 diabetes (including diabetes with poor glycemic control despite conventional oral or parenteral antidiabetic medications) .
Thus, thorough treatment of hyperglycemia can reduce the incidence of chronic disorders, but many diabetics have limited long-term efficacy, tolerability and administration of conventional antihyperglycemia treatments. It is still inadequate because of inconvenience.
In addition, obesity, overweight or weight gain (eg as a side effect or adverse effect of some conventional anti-diabetic medications) further complicates the treatment of diabetes and its microvascular or macrovascular complications.
This high incidence of treatment failure is associated with a high rate of long-term hyperglycemia-related complications or chronic disorders in diabetic patients (small and large vessel complications such as diabetic nephropathy, retinopathy or neuropathy, or cerebrovascular or cardiac It is a major contributor to vascular complications, including myocardial infarction, stroke or death.

Oral antidiabetics conventionally used in therapy (eg, first or second line therapy, and / or single agent or combination therapy (initial or additional)) include, but are not limited to, metformin, Examples include sulfonylurea drugs, thiazolidinediones, glinides, and α-glucosidase inhibitors.
As parenteral (typically injectable) anti-diabetics conventionally used in therapy (eg first-line or second-line therapy and / or single agent or combination therapy (initial or additional)) , But not limited to, GLP-1 or GLP-1 analog, and insulin or insulin analog.

However, the use of these conventional antidiabetic or antihyperglycemic agents can be associated with various adverse effects. For example, metformin may be associated with lactic acidosis or gastrointestinal side effects, sulfonylureas, glinides, and insulin or insulin analogs may be associated with hypoglycemia and weight gain, and thiazolidinediones are edema , Fractures, weight gain, and heart failure / heart effects, and α-glucosidase blockers and GLP-1 or GLP-1 analogs may cause adverse gastrointestinal effects (eg, dyspepsia, release or Diarrhea, or nausea or vomiting).
Accordingly, there remains a need in the art to provide effective, safe and tolerable treatments.
Furthermore, in the treatment of type 2 diabetes, it is necessary to treat the condition effectively, avoid complications inherent in the condition, and slow the progression of the disease.
Furthermore, in the treatment of type 2 diabetes, diabetic phenotype, blood glucose and / or metabolic control, and / or continuous improvement of (blood) glucose profile (preferably over long-term and / or chronic treatment). is necessary.
In addition, anti-diabetic treatment is a treatment option for diabetic patients who have advanced complications such as renal dysfunction or are at risk of developing complications, as well as preventing long-term complications often seen in late diabetes It is still necessary.

Furthermore, there remains a need to prevent or reduce the risk of adverse effects associated with conventional anti-diabetic therapies.
In addition, obese patients with or without diabetes, especially to reduce the weight of such patients, facilitate weight loss, control weight, maintain weight, and / or prevent weight gain There remains a need in the art to provide an effective, safe and tolerable treatment for.
Furthermore, in the management of the dual epidemic of diabetes and obesity ("diabetes obesity"), treating or preventing these conditions together, particularly achieving long-term weight loss and weight control, and glycemic control The goal is to find a safe, tolerable, and effective treatment in improving

Within the scope of the present invention, certain DPP-4 inhibitors as indicated herein (preferably linagliptin), as well as one or more other active agents as indicated herein (eg GLP-1 receptor) Combined with agonists, particularly short-acting GLP-1, GLP-1 mimics, or GLP-1 analogs such as exenatide or natural GLP-1 and / or α-glucosidase inhibitors such as voglibose)) A combination medicament, pharmaceutical composition, use or method according to the invention of a DPP-4 inhibitor (preferably linagliptin) that may be made suitable for the purposes of the invention and / or Having characteristics that make it suitable to meet one or more of the needs mentioned in.
The enzyme DPP-4 (dipeptidyl peptidase IV), also known as CD26, is a serine protease that has been found to cleave dipeptides from the N-terminus of many proteins with proline or alanine residues at the N-terminus. is there. This property makes DPP-4 inhibitors interfere with the plasma levels of biologically active peptides (including GLP-1 peptides) and is considered a promising drug for the treatment of diabetes.

  For example, DPP-4 inhibitors and their use are described in WO2002 / 068420, WO2004 / 018467, WO2004 / 018468, WO2004 / 018469, WO2004 / 041820, WO2004 / 046148, WO2005 / 051950, WO2005 / 082906, WO2005 / 063750, WO2005. WO08 / 02246, WO2006 / 027204, WO2006 / 029769, WO2007 / 014886; WO2004 / 050658, WO2004 / 111105, WO2005 / 058901, WO2005 / 097798; WO2006 / 06163, WO2007 / 071738, WO2008 / 017670; WO2007 / 17772; , WO It disclosed in 007/128761 or WO2009 / 121945.

DPP-4 inhibitors within the meaning of the present invention include, but are not limited to, any of the DPP-4 inhibitors described above and below, preferably oral and / or subcutaneously active DPP-4 inhibitors Is mentioned.
GLP-1 receptor agonists within the meaning of the present invention include, but are not limited to, exogenous GLP-1 (natural or synthetic), GLP-1 analogs, GLP-1 mimetics, and GLP- Any other substance that promotes signal transduction by one receptor (peptidic or non-peptidic, eg small molecule), preferably any of their short acting types, eg short acting GLP- 1, GLP-1 mimetics, or GLP-1 analogs such as exenatide or native GLP-1.

Within the context of the present invention, a short-acting GLP-1, GLP-1 mimetic, or GLP-1 analog has a short half-life, such as exendin-4 or exenatide or natural GLP-1 (or at least Refers to such drugs (subcutaneously administered twice daily).
Thus, short-acting GLP-1 receptor agonists herein have a duration of action of less than 24 hours, such as exenatide or natural GLP-1, or less than about 13 hours, less than 10 hours, 5 hours It may be mentioned that the drug has a short half-life of less than or less than 2.5 hours (eg about 2.4 hours or less) or is administered subcutaneously at least twice daily.
As long as all of these agents exhibit the desired properties and functions, all of these agents are contemplated and are within the scope of the present invention.

In a first embodiment (embodiment A), the DPP-4 inhibitor in the context of the present invention has the formula (I)
Or formula (II)
Or formula (III)
Or formula (IV)
Wherein R1 is ([1,5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) Methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl, or (4 , 6-Dimethyl-pyrimidin-2-yl) methyl and R2 are 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) Represents -amino-propyl) -methylamino)
Any DPP-4 inhibitor, or a pharmaceutically acceptable salt thereof.

With respect to the first embodiment (embodiment A), preferred DPP-4 inhibitors are the following compounds or pharmaceutically acceptable salts thereof:
1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl ) -Xanthine (compare WO 2004/018468, Example 2 (142))

1-[([1,5] naphthyridin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidine-1- Yl) -xanthine (compare WO 2004/018468, Example 2 (252)):

1-[(quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl) -xanthine ( Compare to WO 2004/018468, Example 2 (80)):

2-((R) -3-Amino-piperidin-1-yl) -3- (but-2-ynyl) -5- (4-methyl-quinazolin-2-ylmethyl) -3,5-dihydro-imidazo [4,5-d] pyridazin-4-one (compare WO 2004/050658, Example 136):

1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-[(2-amino-2-methyl-propyl) -methyl Amino] -xanthine (compare WO 2006/029769, Example 2 (1)):

1-[(3-Cyano-quinolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl ) -Xanthine (compare WO 2005/085246, Example 1 (30)):

1- (2-cyano-benzyl) -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl) -xanthine (WO 2005/085246) Compare with Example 1 (39)):

1-[(4-Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-[(S)-(2-amino-propyl) -methyl Amino] -xanthine (compare WO 2006/029769, Example 2 (4)):

1-[(3-Cyano-pyridin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl ) -Xanthine (compare WO 2005/085246, Example 1 (52)):

1-[(4-Methyl-pyrimidin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl ) -Xanthine (compare WO 2005/085246, Example 1 (81)):

1-[(4,6-Dimethyl-pyrimidin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidine-1 -Yl) -xanthine (compare WO 2005/085246, Example 1 (82)):

1-[(Quinoxalin-6-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl) -xanthine ( (Compare WO 2005/085246, Example 1 (83)):

  These DPP-4 inhibitors are distinguished from structurally similar DPP-4 inhibitors. Because they combine very good efficacy and long-term action with favorable pharmacological properties, receptor selectivity, and favorable side effect profile, or when combined with other pharmaceutically active substances, This provides an unexpected therapeutic benefit or improvement. These adjustments are disclosed in the aforementioned publications.

In a second embodiment (embodiment B), the DPP-4 inhibitor in the context of the present invention is sitagliptin, vildagliptin, saxagliptin, alogliptin, gemigliptin, omalipliptin, evogliptin,
(2S) -1-{[2- (5-methyl-2-phenyl-oxazol-4-yl) -ethylamino] -acetyl} -pyrrolidine-2-carbonitrile,
(2S) -1-{[1,1, -dimethyl-3- (4-pyridin-3-yl-imidazol-1-yl) -propylamino] -acetyl} -pyrrolidine-2-carbonitrile,
(S) -1-((2S, 3S, 11bS) -2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinoline -3-yl) -4-fluoromethyl-pyrrolidin-2-one,
(3,3-difluoropyrrolidin-1-yl)-((2S, 4S) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) pyrrolidin-2-yl) methanone,
(1 ((3S, 4S) -4-amino-1- (4- (3,3-difluoropyrrolidin-1-yl) -1,3,5-triazin-2-yl) pyrrolidin-3-yl)- 5,5-difluoropiperidin-2-one,
(2S, 4S) -1- {2-[(3S, 1R) -3- (1H-1,2,4-triazol-1-ylmethyl) cyclopentylamino] -acetyl} -4-fluoropyrrolidine-2-carbo Nitrile,
(R) -2- [6- (3-Amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl] -4-fluoro- Benzonitrile,
5-{(S) -2- [2-((S) -2-cyano-pyrrolidin-1-yl) -2-oxo-ethylamino] -propyl} -5- (1H-tetrazol-5-yl) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene-2,8-dicarboxylic acid bis-dimethylamide,
3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine,
[(2R) -1-{[(3R) -pyrrolidin-3-ylamino] acetyl} pyrrolidin-2-yl] boronic acid,
(2S, 4S) -1- [2-[(4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile,
2-({6-[(3R) -3-amino-3-methylpiperidin-1-yl] -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo [3,2-d] pyrimidin-5-yl} methyl) -4-fluorobenzonitrile,
6-[(3R) -3-Amino-piperidin-1-yl] -5- (2-chloro-5-fluoro-benzyl) -1,3-dimethyl-1,5-dihydro-pyrrolo [3,2- d] pyrimidine-2,4-dione, and (S) -2-methylpyrazolo [1,5-a] primidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl) -2-oxoethyl Amino] -2-methylpropyl} amide,
A DPP-4 inhibitor selected from: or a pharmaceutically acceptable salt thereof.

  Among the aforementioned DPP-4 inhibitors of embodiment A of the present invention, a more preferred DPP-4 inhibitor is 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine, especially its free base (also known as linagliptin or BI1356).

Further DPP-4 inhibitors may include the following compounds:
Sitagliptin (MK-0431) having the following structural formula A is (3R) -3-amino-1- [3- (trifluoromethyl) -5,6,7,8-tetrahydro-5H- [1, 2,4] triazolo [4,3-a] pyrazin-7-yl] 4- (2,4,5-trifluorophenyl) butan-1-one, also known as (2R) -4-oxo-4- [3 -(Trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] -1- (2,4,5-trifluorophenyl) Butan-2-amine.
In one embodiment, sitagliptin is its dihydrogen phosphate form, ie sitagliptin phosphate. In a further embodiment, the sitagliptin phosphate is in the form of a crystalline anhydride or monohydrate. The class of this embodiment refers to sitagliptin phosphate monohydrate. Sitagliptin free base, and pharmaceutically acceptable salts thereof, are disclosed in US Pat. No. 6,699,871 and Example 7 of WO 03/004498. Crystalline sitagliptin phosphate monohydrate is disclosed in WO2005 / 003135 and WO2007 / 050485.

Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.
Sitagliptin tablets are commercially available under the trade name Januvia®. Sitagliptin / metformin combination tablets are commercially available under the trade name Janumet®.

-Vildagliptin (LAF-237) having the structure of the following structural formula B is (2S)-{[(3-hydroxyadamantan-1-yl) amino] acetyl} pyrrolidine-2-carbonitrile, also known as (S)- 1-[(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine.
Vildagliptin is disclosed in detail in US Pat. No. 6,166,063 and Example 1 of WO 00/34241. Specific salts of vildagliptin are disclosed in WO2007 / 019255. A crystalline form of vildagliptin and tablets of vildagliptin are disclosed in WO 2006/078593. Vildagliptin can be formulated as described in WO00 / 34241 or WO2005 / 067976. A vildagliptin formulation with improved release is described in WO 2006/135723.

Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.
Vildagliptin tablets will be marketed under the trade name Galvus®. A tablet of the vildagliptin / metformin combination is commercially available under the trade name Eucreas®.
-Saxagliptin (BMS-477118) having the following structural formula C is (1S, 3S, 5S) -2-{(2S) -2-amino-2- (3-hydroxyadamantan-1-yl) acetyl}- 2-Azabicyclo [3.1.0] hexane-3-carbonitrile, also known as (S) -3-hydroxyadamantylglycine-L-cis-4,5-methanoproline nitrile.
Saxagliptin is described in detail in US Pat. No. 6,395,767 and in Example 60 of WO 01/68603.

  In one embodiment, saxagliptin is in the form of its HCl salt or its monobenzoate salt, as disclosed in WO 2004/052850. In a further embodiment, saxagliptin is in the free base form. In a further embodiment, saxagliptin is in the form of the free base monohydrate, as disclosed in WO2004 / 052850. Crystalline forms of saxagliptin HCl salt and free base are disclosed in WO2008 / 131149. A method for preparing saxagliptin is also disclosed in WO2005 / 106011 and WO2005 / 115982. Saxagliptin can be formulated into tablets as described in WO2005 / 117841.

Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.
-Alogliptin (SYR-322) having the following structural formula E is 2-({6-[(3R) -3-aminopiperidin-1-yl] -3-methyl-2,4-dioxo-3,4 -Dihydro-2H-pyrimidin-1-yl} methyl) benzonitrile.

Alogliptin is disclosed in detail in US 2005/261271, EP 1586571, and WO 2005/095381. In one embodiment, alogliptin is in the form of its benzoate, its hydrochloride or its tosylate, as disclosed in WO2007 / 035629. This class of embodiments relates to alogliptin benzoate. The polymorph of alogliptin benzoate is disclosed in WO2007 / 035372. The preparation method of alogliptin is disclosed in WO2007 / 112368, and in detail in WO2007 / 035629. Alogliptin (ie, its benzoate salt) can be formulated and administered into tablets as described in WO2007 / 033266. The solid preparation of alogliptin / pioglitazone, and its preparation and use is described in WO2008 / 093882. The solid preparation of alogliptin / metformin, and its preparation and use are described in WO2009 / 011451.
Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-(2S) -1-{[2- (5-Methyl-2-phenyl-oxazol-4-yl) ethylamino] acetyl} pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof, preferably mesyl Acid salt, or (2S) -1-{[1,1, -dimethyl-3- (4-pyridin-3-yl-imidazol-1-yl) propylamino] acetyl} -pyrrolidine-2-carbonitrile or its Pharmaceutically acceptable salts:
These compounds and methods for their preparation are disclosed in WO03 / 037327. The mesylate salt of the former compound and its crystalline polymorph are disclosed in WO 2006/100181. The fumarate salt of the latter compound and its crystalline polymorph are disclosed in WO2007 / 071576. These compounds can be formulated into pharmaceutical compositions as described in WO2007 / 017423.
Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-(S) -1-((2S, 3S, 11bS) -2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] Isoquinolin-3-yl) -4-fluoromethyl-pyrrolidin-2-one (also known as carmegliptin) or a pharmaceutically acceptable salt thereof:
This compound and its method of preparation are disclosed in WO 2005/000848. Methods for preparing this compound (specifically its dihydrochloride salt) are also disclosed in WO2008 / 031749, WO2008 / 031750 and WO2008 / 055814. This compound can be formulated into a pharmaceutical composition as described in WO2007 / 017423.

Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.
-(3,3-difluoropyrrolidin-1-yl)-((2S, 4S) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) pyrrolidin-2-yl) methanone (also known as gosogliptin) Or a pharmaceutically acceptable salt thereof:
This compound and its method of preparation are disclosed in WO2005 / 116014 and US7291618.
Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-(1 ((3S, 4S) -4-amino-1- (4- (3,3-difluoropyrrolidin-1-yl) -1,3,5-triazin-2-yl) pyrrolidin-3-yl) -5,5-difluoropiperidin-2-one, or a pharmaceutically acceptable salt thereof:
This compound and its method of preparation are disclosed in WO2007 / 148185 and US2007029976. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-(2S, 4S) -1- {2-[(3S, 1R) -3- (1H-1,2,4-triazol-1-ylmethyl) cyclopentylamino] acetyl} -4-fluoropyrrolidine-2-carbo Nitrile (also known as melogliptin), or a pharmaceutically acceptable salt thereof:
This compound and its method of preparation are disclosed in WO2006 / 040625 and WO2008 / 001195. In particular, the claimed salts include methane sulfonate and p-toluene sulfonate. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-(R) -2- [6- (3-Amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl] -4-fluoro Benzonitrile, or a pharmaceutically acceptable salt thereof:
This compound and methods for its preparation and use are disclosed in WO2005 / 095381, US20070530530, WO2007 / 033350, WO2007 / 035629, WO2007 / 074884, WO2007 / 112368, WO2008 / 033851, WO2008 / 114800, and WO2008 / 114807. In particular, the claimed salts include succinate (WO2008 / 0667465), benzoate, benzenesulfonate, p-toluenesulfonate, (R) -mandelate, and hydrochloride. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-5-{(S) -2- [2-((S) -2-Cyano-pyrrolidin-1-yl) -2-oxo-ethylamino] -propyl} -5- (1H-tetrazol-5-yl ) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene-2,8-dicarboxylic acid bisdimethylamide, or a pharmaceutically acceptable salt thereof:
This compound and method of preparation are disclosed in WO 2006/116157 and US 2006/270701. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-3-{(2S, 4S) -4- [4- (3-Methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine (also known as tenerigliptin) Or a pharmaceutically acceptable salt thereof:
This compound and its method of preparation are disclosed in WO 02/14271. Specific salts are disclosed in WO 2006/088129 and WO 2006/118127 (in particular including hydrochlorides and hydrobromides). Combination therapy using this compound is described in WO 2006/129785. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-[(2R) -1-{[(3R) -pyrrolidin-3-ylamino] acetyl} pyrrolidin-2-yl] boronic acid (also known as dutogliptin), or a pharmaceutically acceptable salt thereof:
This compound and its method of preparation are disclosed in WO2005 / 047297, WO2008 / 1099681 and WO2009 / 009751. Specific salts are disclosed in WO2008 / 027273 (including citrate and tartrate). The formulation of this compound is described in WO2008 / 144730. A formulation of dutogliptin (its tartrate salt) and metformin is described in WO2009 / 091663. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-(2S, 4S) -1- [2-[(4-Ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile (also known as Bisegliptin) Or a pharmaceutically acceptable salt thereof:
This compound and its method of preparation are disclosed in WO2005 / 077541, US2008 / 146818, and WO2008 / 114857. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-2-({6-[(3R) -3-amino-3-methylpiperidin-1-yl] -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H- Pyrrolo [3,2-d] pyrimidin-5-yl} methyl) -4-fluorobenzonitrile or a pharmaceutically acceptable salt thereof, or 6-[(3R) -3-amino-piperidin-1-yl] -5- (2-chloro-5-fluoro-benzyl) -1,3-dimethyl-1,5-dihydro-pyrrolo [3,2-d] pyrimidine-2,4-dione or a pharmaceutically acceptable salt thereof salt;
These compounds and methods for their preparation are disclosed in WO2009 / 084497 and WO2006 / 068163, respectively. Combination therapy using the latter of these two compounds is described in WO2009 / 128360. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.

-(S) -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl) -2-oxoethylamino] -2-methylpropyl} amide ( Also known as anagliptin), or a pharmaceutically acceptable salt thereof:
This compound and its method of preparation are disclosed in WO 2004/067509. Combination therapy using this compound is described in WO2009 / 139362. Thus, reference is made to these documents for details regarding, for example, methods for preparing, formulating or using the compounds or salts thereof.
Preferably, the DPP-4 inhibitor of the present invention is linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, teneligliptin, anagliptin, gemigliptin and dutogliptin, or one of the DPP-4 inhibitors described herein. Selected from the group consisting of pharmaceutically acceptable salts, or prodrugs thereof.

A particularly preferred DPP-4 inhibitor to be emphasized in the present invention is linagliptin. As used herein, the term “linagliptin” refers to linagliptin or a pharmaceutically acceptable salt thereof, including hydrates and solvates thereof and crystalline forms thereof, preferably linagliptin is 1-[(4- Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine. The crystalline form is described in WO2007 / 128721. A method for producing linagliptin is described, for example, in patent applications WO 2004/018468 and WO 2006/048427. Linagliptin is distinguished from structurally similar DPP-4 inhibitors. Because linagliptin combines very good efficacy and long-term action with favorable pharmacological properties, receptor selectivity, and favorable side effect profile, or monotherapy or dual or triple therapy Because it provides an unexpected therapeutic benefit or improvement.
For the avoidance of any doubt, the disclosures of each of the above cited references and the following references cited above in connection with specific DPP-4 inhibitors are specifically incorporated herein by reference in their entirety.

One embodiment of the present invention is DPP-4 suitable for use in the treatment and / or prevention of metabolic diseases (particularly type 2 diabetes) in patients further suffering from renal disease, renal dysfunction or renal dysfunction, The DPP-4 inhibitor is administered to the patient at the same dose level as a patient with normal renal function, and thus, for example, the DPP-4 inhibitor is adjusted to reduce administration for impaired renal function It relates to a DPP-4 inhibitor, characterized in that it does not have to be done.
For example, DPP-4 inhibitors according to the present invention (especially those that may be suitable for patients with reduced renal function) preferably have a relatively broad active metabolite (eg, greater than about 100 times). It may be an oral DPP-4 inhibitor that has a therapeutic concentration range and / or is excreted primarily by liver metabolism or biliary excretion (preferably without further burden on the kidney).

More particularly, DPP-4 inhibitors according to the present invention (especially those that may be suitable for patients with reduced renal function) have a relatively broad therapeutic range (eg, greater than about 100 times) (preferably May be an oral DPP-4 inhibitor that meets one or more of the following pharmacokinetic properties (preferably at an oral therapeutic dose level):
The DPP-4 inhibitor is substantially or predominantly excreted via the liver (eg, greater than 80% or greater than 90% of the oral dose) and / or substantially free of renal excretion or major The amount measured by following the excretion of an oral dose of a radiolabeled carbon ( 14 C) substance, for example, is less than 10%, preferably 7% of the measured oral dose. Less than)
-DPP-4 inhibitors are excreted largely unchanged as parent drug (for example, the average excreted radioactivity in urine and stool after oral dosing of radiolabeled carbon ( 14 C) substance is greater than 70 Or greater than 80%, preferably 90%) and / or is not substantially excreted by metabolism, or is excreted only to a small extent (eg less than 30%, or less than 20%, preferably 10%),
-One or more (major) metabolites of DPP-4 inhibitors are pharmacologically inactive. For example, the major metabolite does not bind to the target enzyme DPP-4 and is optionally excreted rapidly compared to the parent compound (eg, the elimination half-life of the metabolite is 20 hours or less, preferably about 16 hours or less For example, 15.9 hours).

  In one embodiment, the plasma (major) metabolite of a DPP-4 inhibitor (which may be pharmacologically inactive) having a 3-aminopiperidin-1-yl substituent is 3-aminopiperidin-1 The amino group of the yl moiety is replaced by a hydroxyl group to form a 3-hydroxy-piperidin-1-yl moiety (eg a 3- (S) -hydroxypiperidin-1-yl moiety formed by inversion of the configuration of the chiral center ).

Furthermore, the properties of the DPP-4 inhibitor according to the present invention may be one or more of the following. Rapid achievement of steady state (eg steady state plasma levels (reaching over 90% of steady state plasma concentration) between days 2 and 5 of treatment with oral therapeutic dose levels), small accumulation (eg oral treatment) Maintain a long-term effect on DPP-4 inhibition (e.g. oral therapy) when used at a daily average accumulation ratio RA, AUC of 1.4 or less) and / or preferably once daily. At the dose level, DPP-4 inhibition is almost complete (> 90%), more than 80% inhibition over a 24 hour interval after taking a daily oral therapeutic drug dose), at the therapeutic dose level 2 hours postprandial blood glucose excursion is greater than 80% (already on the first day of treatment) and the cumulative amount of unchanged parent compound excreted in the urine on the first day is administered Less than 1% of the amount, steady state In increasing to about 3-6% or less.

Thus, for example, a DPP-4 inhibitor according to the present invention provides that the DPP-4 inhibitor has primarily a non-renal excretion pathway, i.e., the DPP-4 inhibitor is not substantially excreted via the kidney, or Only a small amount (eg less than 10%, preferably less than 7%, eg about 5%) of the administered oral dose, preferably the oral therapeutic dose, is excreted (eg elimination of the oral dose of radiolabeled carbon ( 14 C) substance). (Measured by tracking).
Further, the DPP-4 inhibitor according to the present invention is such that the DPP-4 inhibitor is substantially or mainly excreted via the liver, bile or stool (eg, an oral dose of a radiolabeled carbon ( 14 C) substance). As measured by tracking discharge).

Furthermore, the DPP-4 inhibitor according to the present invention is:
The DPP-4 inhibitor is excreted unchanged as a parent drug mainly (for example, the average radioactivity excreted in urine and stool after oral administration of radiolabeled carbon ( 14 C) substance is more than 70%, Or more than 80%, preferably 90%)
The DPP-4 inhibitor is not substantially excreted or excreted to a small extent via metabolism, and / or the main metabolite of the DPP-4 inhibitor is pharmacologically inactive, or It may be characterized by having a relatively wide therapeutic concentration range.

Furthermore, the DPP-4 inhibitor according to the present invention is:
The DPP-4 inhibitor does not significantly impair glomerular and / or tubular function of type 2 diabetic patients with chronic renal failure (eg, mild, moderate or severe renal dysfunction or end-stage renal disease); And / or the trough level of the DPP-4 inhibitor in the plasma of type 2 diabetic patients with mild or moderate renal dysfunction is comparable to the level of patients with normal renal function, and / or DPP-4 inhibitors adjust dose in type 2 diabetic patients with impaired renal function (eg, mild, moderate or severe renal dysfunction or end stage renal disease, preferably regardless of stage of renal dysfunction) It may be characterized by not being necessary.

Furthermore, the DPP-4 inhibitor according to the present invention is:
The DPP-4 inhibitor achieves its minimal effective dose at a dose that results in more than 50% inhibition of DPP-4 activity in the trough (24 hours after the last dose) in more than 80% of patients, And / or achieve the full therapeutic dose at a dose that results in more than 80% inhibition of DPP-4 activity in the trough (24 hours after the last dose) in more than 80% of patients. May be a feature.
Furthermore, the DPP-4 inhibitors according to the present invention may be used in patients with type 2 diabetes who have been diagnosed with renal dysfunction or renal complications and / or are at risk of developing renal complications, such as diabetic nephropathy (chronic and progressive). It may be characterized by being suitable for use in patients with or at risk for renal dysfunction, albuminuria, proteinuria, fluid retention (including edema), and / or hypertension in the body).

In monitoring diabetes treatment, the HbA1c value, ie the product of non-enzymatic glycosylation of hemoglobin B chain, is of particular importance. Since its formation is substantially dependent on blood glucose levels and red blood cell lifetimes, HbA1c in the sense of “blood glucose memory” reflects the average blood glucose level for the preceding 4-12 weeks. Diabetic patients whose HbA1c levels have been well controlled by more thorough diabetes treatment for extended periods of time (ie, less than 6.5% of the total hemoglobin in the sample) are much better protected from diabetic microangiopathy. The available treatments for diabetes can give diabetics an average improvement in HbA1c levels on the order of 1.0-1.5%. This reduction in HbA1c levels is not sufficient to bring all diabetics HbAlc to a desired target range of less than 7.0%, preferably less than 6.5%, more preferably less than 6%.
Within the meaning of the present invention, inadequate or insufficient glycemic control is especially the case when the patient is more than 6.5%, in particular more than 7.0%, more preferably more than 7.5%, in particular more than 8%. It means a state showing the HbA1c value. Embodiments of patients with inadequate or insufficient glycemic control include, but are not limited to, patients with HbAlc values of 7,5-10% (7.5-11% in another embodiment). Special dependent embodiments of patients undergoing inadequate control refer to patients with poor glycemic control, including, but not limited to, patients with HbA1c values of 9% or higher.

  In glycemic control, in addition to improving HbA1c levels, other treatment goals recommended for patients with type 2 diabetes are normal or as near as normal to fasting plasma glucose (FPG) levels and postprandial plasma glucose (PPG) levels It is to improve. The recommended desired target range for pre-meal (fasting) plasma glucose is 70-130 mg / dL (or 90-130 mg / dL) or less than 110 mg / dL, and less than 180 mg / dL for plasma glucose 2 hours after meal Or less than 140 mg / dL.

  In one embodiment, a diabetic patient within the meaning of the present invention may include a patient who has never been treated with an anti-diabetic drug (drug-untreated patient). Accordingly, in one embodiment, the treatment methods described herein may be used for non-drug patients. In another embodiment, a diabetic patient within the meaning of the present invention is glycemic control for, for example, one, two or more of the conventional oral and / or parenteral antidiabetic agents shown herein. (Eg, metformin, thiazolidinediones (especially pioglitazone), sulfonylureas, glinides, GLP-1 or GLP-1 analogs, insulin or insulin analogs, or α-glucosidase inhibitors (single agent) ) Despite therapy or metformin / sulfonylurea, metformin / thiazolidinedione (especially pioglitazone), sulfonylurea / α-glucosidase inhibitors, pioglitazone / sulfonylurea, metformin / insulin, pioglitazone / insulin, or sulfonyluria Includes patients with advanced or late type 2 diabetes (including patients who have failed conventional anti-diabetic therapy), such as those with poor glycemic control despite dual / insulin combination therapy But you can. Thus, in one embodiment, the treatment methods described herein are treatments such as, for example, conventional oral and / or parenteral antidiabetic monotherapy or dual or triple combination therapy as described herein. It may be used in patients who have experienced the law.

Further embodiments of diabetic patients within the meaning of the present invention are:
-Patients who are contraindicated for metformin therapy, for example patients who have one or more contraindications to metformin therapy by label, for example
Kidney disease, kidney damage or kidney failure (eg as specified by product information of metformin approved in some areas),
dehydration,
Unstable or acute congestive heart failure,
At least one contraindicated patient selected from acute or chronic metabolic acidosis and hereditary galactose intolerance, and one or more intolerable side effects caused by metformin, particularly gastrointestinal side effects associated with metformin Suffering patient, for example
It refers to patients who are unsuitable for metformin therapy, including those suffering from at least one gastrointestinal side effect selected from nausea and vomiting diarrhea intestinal gas and severe abdominal discomfort.

  Further embodiments of diabetic patients that may be suitable for the treatment methods of the present invention include, but are not limited to, diabetic patients for whom normal metformin therapy is not appropriate, such as reduced tolerability, intolerance, or contraindications to metformin. Or diabetic patients (including elderly patients, including 60-65 years old and older) in need of dose-reduced metformin therapy due to (mild) impairment / reduction of renal function.

  Further embodiments of patients within the meaning of the invention (eg of diabetes and / or obesity) are for example increased serum creatinine levels (eg serum creatinine values above the upper limit of normal age, eg 130 μmol / 1 to 150 μmol / l, or 1.5 mg / dl or more (136 μmol / l or more) and 1.4 mg / dl or more (124 μmol / l or more) in women or abnormal creatinine clearance (eg, 30 ml / min to 60 ml / Means patients with renal disease, renal dysfunction, or impaired or impaired renal function (including mild, moderate and severe renal dysfunction), as suggested by minute glomerular filtration rate (GFR) To do.

  In this context, for a more detailed example, mild renal dysfunction may result in serum creatine levels of, for example, 50-80 ml / min creatinine clearance (1.7 mg / dL or less for men and 1.5 mg / dL or less for women). Moderate renal dysfunction, for example 30-50 ml / min creatinine clearance (above 1.7 mg / dL to less than 3.0 mg / dL in men, and 1. Severe renal dysfunction may be suggested by a creatinine clearance (eg, 3.0 mg / dL in men) of less than 30 ml / min, which may be suggested by serum creatine levels greater than 5 mg / dL and below 2.5 mg / dL. End stage kidneys, which may be suggested by (and approximately corresponds to a serum creatine value greater than 2.5 mg / dL in women) Patients patients require dialysis (eg hemodialysis or peritoneal dialysis).

For other more detailed examples, patients with renal disease, renal dysfunction or renal dysfunction include patients with chronic renal failure or dysfunction, which includes glomerular filtration rate (GFR, ml / min / 1 .73 m 2 ) can be divided into five stages. Stage 1 is characterized by over 90 normal GFR plus persistent albuminuria or known organic or hereditary renal disease; stage 2 is a mild decrease in GFR that represents mild renal dysfunction (60-89); stage 3 is characterized by a moderate decrease in GFR (GFR 30-59), which represents moderate renal dysfunction; stage 4 is severe renal dysfunction Characterized by a severe reduction in GFR (GFR 15-29); the final fifth phase is by less than 15 GFR, which requires dialysis or represents established renal failure (end-stage renal disease, ESRD) Characterized.

Further embodiments of patients within the meaning of the present invention (eg diabetes and / or obesity) include renal complications such as diabetic nephropathy (chronic and progressive renal dysfunction, albuminuria, proteinuria, body fluids in the body). Means patients with type 2 diabetes and / or obesity who develop or are at risk of developing retention (including edema) and / or hypertension.
Examples of metabolic disorders or diseases suitable for the treatment method of the present invention include, but are not limited to, type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, Postprandial hyperglycemia, postabsorption hyperglycemia, adult latent autoimmune diabetes (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, high non-ester fatty acid blood , Fasting or postprandial hyperlipidemia, eg postprandial lipemia (eg postprandial hypertriglyceridemia), hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, nonalcoholic Can include fatty liver disease (NAFLD), diabetic retinopathy, neuropathy, nephropathy, polycystic ovary syndrome, and / or metabolic syndrome.

The present invention further includes
To a patient in need thereof (eg, a patient described herein, eg, a patient with overweight, obesity and / or diabetes),
In particular for patients who need further caloric intake, excessive dietary energy intake, body weight, total fat mass, total fat percentage, visceral fat and / or reduced overeating, promoting the reduction or preventing the increase and / or food Especially for patients who need to change and / or reduce their intake, the foods are rich in fat and / or carbohydrates (eg high calorie, delicious, sweet and / or fatty foods) For example, foods with a high glycemic index and / or monosaccharides and / or disaccharides make up the majority of the total amount of carbohydrates and / or the majority of the total amount of energy is derived from fat and / or Reduced intake and / or health of high-calorie (delicious, fat and / or carbohydrate rich) foods Away from bad food (eg as described herein), to a food or taste preference or selection of food to a healthy food (eg as described herein) Patients and / or health who are in need of further adjustment or transition and who need to reduce the amount of unhealthy and / or high calorie (eg, delicious, fat and / or carbohydrate rich) food intake Such as patients who need to increase the amount of good and / or low calorie food intake

The following methods-eg type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), fasting blood glucose deficiency (IFG), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, adult latent autoimmune diabetes (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyper-NEFA, postprandial hyperlipidemia (eg postprandial hypertriglyceridemia), hypertension, atheroma Metabolic disorders such as atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, nonalcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome and / or metabolic syndrome Preventing the disease, delaying its progression, delaying its onset or treating it,
-Improving and / or maintaining glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose, post-absorption plasma glucose and / or glycosylated hemoglobin HbA1c, or despite treatment, glycemic control Preventing or aggravating, reducing the need for insulin therapy or increasing HbA1c, reducing its risk, delaying its progression, delaying its onset or treating it;
-Preventing, delaying, delaying the onset of prediabetes, impaired glucose tolerance (IGT), fasting blood glucose deficiency (IFG), insulin resistance and / or metabolic syndrome to type 2 diabetes Delaying or reversing its progression;
-Nephropathy, micro or macroalbuminuria, proteinuria, retinopathy, cataract, neuropathy, learning or memory impairment, neurodegeneration or cognitive impairment, cardiovascular or cerebrovascular disease, tissue illness, including microvascular and macrovascular diseases Blood, diabetic foot lesion or ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure Preventing diabetes complications such as heart rhythm disorders, vascular restenosis and / or stroke, reducing its risk, delaying its progression, delaying its onset or treating it;

Reducing body weight and / or body fat and / or liver fat and / or muscle cell fat or preventing weight and / or body fat and / or liver fat and / or muscle cell fat increase or body weight And / or promote the reduction of body fat and / or liver fat and / or muscle cell fat;
-To prevent, delay, delay or treat the onset of pancreatic beta cell degeneration and / or pancreatic beta cell functionality and / or improve pancreatic beta cell functionality To preserve and / or restore and / or to stimulate and / or restore or protect the functionality of pancreatic insulin secretion;
-Preventing, delaying, delaying or treating the onset of nonalcoholic fatty liver disease (NAFLD), including fatty liver, nonalcoholic steatohepatitis (NASH) and / or liver fibrosis (For example, preventing fatty liver, (liver) inflammation and / or abnormal accumulation of liver fat, delaying its progression, delaying its onset, attenuating, treating or reversing it);
-Preventing, delaying its progression, delaying its onset or treating it, which has failed conventional antidiabetic monotherapy or combination therapy;
-Achieving the dose reduction of conventional anti-diabetic medication necessary for sufficient therapeutic effect;
-Reducing the risk of adverse effects (eg hypoglycemia or weight gain) associated with conventional anti-diabetic medications; and / or-maintaining and / or improving insulin sensitivity and / or hyperinsulinemia. And / or certain DPP-4 inhibitors (preferably linagliptin, such as GLP-1 receptor agonists) for use in at least one of the methods for treating or preventing insulin resistance In particular, short-acting GLP-1, GLP-1 mimetics or GLP-1 analogs such as exenatide or native GLP-1 and / or α-glucosidases such as (preferably) voglibose May be combined with one or more other active agents, such as inhibitors)
About.

In certain embodiments, the present invention further includes
Subject (eg, a human subject in need thereof, such as a patient with overweight, obesity and / or diabetes),
How to reduce caloric intake, excessive dietary energy intake, body weight, total body fat mass, total body fat percentage, visceral fat and / or overeating, how to promote the reduction or prevent the increase and / or food intake The method of altering and / or reducing, in particular the food product is rich in fat and / or carbohydrate (eg high calorie, delicious, sweet and / or fatty food), eg having a high glycemic index. And / or foods in which monosaccharides and / or disaccharides constitute the majority of the total amount of carbohydrates and / or most of the total amount of energy is derived from fat and / or high calorie (delicious (And fat and / or carbohydrate rich) food intake and / or health benefits Adjust food or taste preferences or food choices to healthy foods (eg, as described herein) away from food products (eg, as described herein) Or a method of migrating, a method of reducing the amount of unhealthy and / or high calorie (e.g. delicious, fat and / or carbohydrate rich) food intake and / or a healthy and / or low calorie food A method of increasing the amount of intake,
An effective amount of a particular DPP-4 inhibitor as defined herein (preferably linagliptin, eg 0.3-10 mg or 0.1-30 mg, preferably 1-5 mg or 1-10 mg Short-acting GLP-1, GLP-1 mimetics such as 2.5 mg or 5 mg per day) and GLP-1 receptor agonists, in particular exenatide or native GLP-1 Or a GLP-1 analog and / or an alpha-glucosidase inhibitor (eg voglibose, miglitol or acarbose, preferably in a low dose form, preferably voglibose) to the subject (eg simultaneously, eg twice a day, eg subcutaneously). Or transdermally).

  It should be understood that within the scope of the present invention, a combination, composition or combined use according to the present invention may envisage simultaneous, sequential or separate administration of the active ingredients or materials.

  In this context, “combination” or “combined” is within the meaning of the invention, without limitation, fixed and, for example, simultaneous use, sequential use or separate use of components or materials. Non-fixed (eg free) form (including kit) and use.

The combined administration of the present invention can be performed by administering together the active ingredients or materials, for example, by administering them simultaneously in a single or two separate formulations or dosage forms. Alternatively, administration can be performed by sequentially administering the active ingredients or materials, for example, sequentially in two separate formulations or dosage forms.
For the combination therapy of the present invention, the active ingredients or materials can be administered separately (implying they are formulated separately) or formulated together (in the same preparation or the same Implied to be formulated in dosage form). Thus, the administration of one element of the combination of the invention may be prior to, concurrent with or after administration of the other elements of the combination.
For example, in one embodiment, for combination therapy according to the invention, a DPP-4 inhibitor and a GLP-1 receptor agonist (especially a short acting GLP-1, GLP-1 such as exenatide or native GLP-1). 1 mimetic or GLP-1 analog) are administered in different formulations or different dosage forms.

In another embodiment, for combination therapy according to the invention, a DPP-4 inhibitor and a GLP-1 receptor agonist (especially short acting GLP-1, GLP-1, such as exenatide or native GLP-1). Mimetics or GLP-1 analogs) are administered in the same formulation or in the same dosage form.
In a further embodiment, for the combination therapy according to the invention, a DPP-4 inhibitor and a GLP-1 receptor agonist (especially a short-acting GLP-1, GLP-1 mimic, such as exenatide or native GLP-1 Body or GLP-1 analog) are administered simultaneously.
In a further embodiment, for the combination therapy according to the invention, the DPP-4 inhibitor is administered orally and is a GLP-1 receptor agonist (especially a short acting GLP-1 such as exenatide or native GLP-1). , GLP-1 mimics or GLP-1 analogs) are administered subcutaneously.
In a further embodiment, for the combination therapy according to the invention, a DPP-4 inhibitor and a GLP-1 receptor agonist (especially a short-acting GLP-1, GLP-1 mimic, such as exenatide or native GLP-1 Body or GLP-1 analog) are each administered subcutaneously.

In a further embodiment, for the combination therapy according to the invention, a DPP-4 inhibitor and a GLP-1 receptor agonist (especially a short-acting GLP-1, GLP-1 mimic, such as exenatide or native GLP-1 Body or GLP-1 analog) is administered simultaneously and each subcutaneously.
The present invention
a) A pharmaceutical composition comprising a DPP-4 inhibitor (preferably linagliptin) as defined herein, and optionally together with one or more pharmaceutically acceptable carriers and / or diluents. And b) GLP-1 receptor agonists as defined herein (especially short acting GLP-1, GLP-1 mimics or GLP-, such as exenatide or native GLP-1) Also provided is a kit of parts or a combination therapy product comprising a pharmaceutical composition comprising one analogue) and optionally together with one or more pharmaceutically acceptable carriers and / or diluents.

The present invention
a) a DPP-4 inhibitor as defined herein (preferably linagliptin) and b) a GLP-1 receptor agonist as defined herein (especially exenatide or native GLP- Short acting GLP-1, GLP-1 mimics or GLP-1 analogs, such as 1)
There is also provided a kit comprising instructions for directing combined (eg simultaneous) use of a DPP-4 inhibitor and a GLP-1 receptor agonist, eg for the purposes of the present invention.

The present invention
a) a DPP-4 inhibitor as defined herein (preferably linagliptin) and b) a GLP-1 receptor agonist as defined herein (especially exenatide or native GLP- Short acting GLP-1, GLP-1 mimics or GLP-1 analogs, such as 1)
A pharmaceutical composition or a fixed dose combination is also provided, which may comprise one or more pharmaceutically acceptable carriers and / or diluents.

The present invention
a) DPP-4 inhibitors as defined herein (preferably linagliptin)
Including
b) GLP-1 receptor agonists as defined herein (especially short acting GLP-1, GLP-1 mimics or GLP-1 analogs such as exenatide or native GLP-1) body)
May include
Also provided is a transdermal or subcutaneous (injectable) pharmaceutical composition, delivery system or device for systemic use, which may include one or more pharmaceutically acceptable carriers and / or diluents.

Furthermore, the present invention provides
DPP-4 inhibitors (preferably linagliptin) as defined herein
Including
GLP-1 receptor agonists as defined herein (especially short acting GLP-1, GLP-1 mimics or GLP-1 analogs such as exenatide or native GLP-1)
May include
May include one or more pharmaceutically acceptable carriers and / or diluents;
It relates to a pharmaceutical composition according to the invention for subcutaneous administration to a patient in need thereof, for example by injection.
Unless otherwise indicated, combination therapy may refer to first selection therapy, second selection therapy or third selection therapy or initial or additional combination therapy or alternative therapy.

With respect to Embodiment A, methods for synthesizing DPP-4 inhibitors according to Embodiment A of the present invention are known to those skilled in the art. Advantageously, a DPP-4 inhibitor according to embodiment A of the present invention may be prepared using synthetic methods as described in the literature. Thus, for example, the purine derivatives of formula (I) are disclosed in WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006 / 048427, the disclosures of which are incorporated herein.
Purine derivatives of formula (II) can be obtained, for example, as described in WO 2004/050658 or WO 2005/110999, the disclosures of which are incorporated herein.

Purine derivatives of the formulas (III) and (IV) can be obtained, for example, as described in WO 2006/068163, WO 2007/071738 or WO 2008/017670, Their disclosures are incorporated herein. The preparation of those DPP-4 inhibitors specifically mentioned above in this specification is disclosed in the publications referred to in connection therewith. Polymorphic crystal modifications and formulations of certain DPP-4 inhibitors are disclosed in WO 2007/128721 or WO 2007/128724, respectively, the disclosures of which are incorporated herein in their entirety. It is. Formulations of certain DPP-4 inhibitors with metformin or other combination partners are described in WO 2009/121945, the disclosure of which is incorporated herein in its entirety.
Typical dosages of linagliptin / metformin IR (immediate release) two fixed combinations (tablets) are 2.5 / 500 mg, 2.5 / 850 mg and 2.5 / 1000 mg, which are 1 It can be administered 1 to 3 times a day, in particular twice a day.
Typical dosages of two fixed combinations (tablets) of linagliptin / metformin XR (long-term release) are 5/500 mg, 5/1000 mg and 5/1500 mg (one tablet each) or 2.5 / 500 mg 2.5 / 750 mg and 2.5 / 1000 mg (two tablets each), which can be administered 1-2 times a day, especially once a day, preferably in the evening with meals.

The present invention relates to use in combination therapy (additional or initial) with metformin (eg, metformin hydrochloride in a total daily dosage of 500 to 2000 mg, such as 500 mg, 850 mg or 1000 mg once or twice daily), Further provided are DPP-4 inhibitors as defined herein.
With respect to Embodiment B, methods for synthesizing the DPP-4 inhibitors of Embodiment B are described in the scientific literature and / or in published patent documents, particularly those cited herein.
The elements of the combination of the present invention can be administered in various ways, for example, oral, buccal, sublingual, enteral, parenteral (eg, transdermal, intramuscular or subcutaneous), by inhalation (eg, inhalation of solutions or powders). , Aerosol), transpulmonary, intranasal (eg spray), intraperitoneal, vaginal, rectal or topical route of administration, suitable for each route of administration, non-toxic pharmaceutically acceptable Can be formulated alone or together in a suitable unit dosage form containing a carrier, adjuvant and vehicle.

In certain embodiments, the DPP-4 inhibitor according to the present invention is preferably administered orally. In another embodiment, a GLP-1 receptor agonist (especially a short-acting GLP-1, GLP-1 mimetic or GLP-1 analog, such as exenatide or native GLP-1) is preferably It is administered by injection (preferably subcutaneously).
Suitable dosages and dosage forms for DPP-4 inhibitors can be determined by one skilled in the art and can include those described herein or in the relevant references.

  For pharmaceutical applications in warm-blooded vertebrates, especially humans, the compounds of the invention are usually administered in dosages from 0.001 to 100 mg / kg body weight, preferably 0.01-15 mg / kg or 0.1-15 mg / kg. In any case, it is used 1 to 4 times a day. For this purpose, the compounds that may be combined with other active substances are, for example, corn starch, lactose, glucose, microcrystalline, together with one or more inert conventional carriers and / or diluents. Cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or hard fat Along with substances or suitable mixtures thereof, they can be incorporated into conventional herbal preparations such as uncoated or coated tablets, capsules, powders, suspensions or suppositories.

Accordingly, a pharmaceutical composition according to the present invention comprising a DPP-4 inhibitor as defined herein is a pharmaceutical composition as described in the art and suitable for the desired route of administration. Prepared by those skilled in the art using acceptable pharmaceutical excipients. Examples of such excipients are diluents, binders, carriers, fillers, lubricants, glidants, crystallization retarders, disintegrants, solubilizers, colorants, pH modifiers, surfactants Including but not limited to agents and emulsifiers.
Oral formulations or dosage forms of the DPP-4 inhibitors of the present invention can be prepared according to known techniques.
Examples of suitable diluents for the compounds according to embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low-substituted hydroxypropylcellulose, mannitol, pregelatinized starch or xylitol.

A pharmaceutical composition or dosage form (eg, an oral tablet) of a DPP-4 inhibitor according to embodiment A of the invention is typically used as an excipient (in addition to the active material), eg, one or more Diluents, binders, disintegrants and lubricants may preferably be included, each as disclosed herein below. In certain embodiments, a disintegrant may be present.
Examples of lubricants suitable for the compounds according to embodiment A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.
Examples of suitable binders for the compounds according to embodiment A are copovidone (copolymers of vinyl pyrrolidone and other vinyl derivatives), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (povidone), Contains pregelatinized starch or low substituted hydroxypropyl cellulose (L-HPC).

Examples of suitable disintegrants for the compounds according to embodiment A include corn starch or crospovidone.
Suitable methods for preparing (oral) preparations or dosage forms of DPP-4 inhibitors according to embodiment A of the present invention include:
Direct compression of the active substance in the powder mixture with a suitable tableting excipient,
Granulation with suitable excipients and subsequent mixing with suitable excipients and subsequent tableting and film coating or filling of powder mixtures or granules into capsules.

A suitable granulation method is
・ After wet granulation in intensive mixer, fluid bed drying,
・ One pot granulation,
Fluid bed granulation or dry granulation with suitable excipients (for example by roller compaction) and subsequent filling into tablets or capsules.
An exemplary composition of a DPP-4 inhibitor according to embodiment A of the present invention (e.g., tablet core) is mannitol, a first diluent, alpha as a second diluent with additional binder properties. A modified starch, copovidone as a binder, corn starch as a disintegrant and magnesium stearate as a lubricant, and may include copovidone and / or corn starch.
The DPP-4 inhibitor tablet according to embodiment A of the present invention may be film coated, preferably the film coating comprises hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide (eg Red and / or yellow).

In a further embodiment, the DPP-4 inhibitor according to the invention is preferably administered by injection (preferably subcutaneously). In another embodiment, a GLP-1 receptor agonist (particularly a short-acting GLP-1, GLP-1 mimetic or GLP-1 analog, such as exenatide or native GLP-1) is preferably Similarly, it is administered by injection (preferably subcutaneously).
GLP-1 receptor agonists (especially short acting GLP-1, GLP-1 mimics or GLP-1 analogs, such as exenatide or native GLP-1) and / or DPP-4 inhibition of the invention Drug injectable formulations (especially subcutaneous use) are used to obtain solutions or suspensions for injection, for example using a suitable liquid carrier, usually containing sterile water, as well as further additives, eg preservatives , PH adjusters, buffers, isotonic agents, solubilizers and / or surfactants may be used and may be prepared according to known pharmaceutical techniques. In addition, injectable formulations can contain additional additives that delay the release of the drug (s), such as salts, solubility modifiers or precipitating agents. In addition, injectable GLP-1 formulations may include agents that stabilize GLP-1 (eg, surfactants).

For example, an injectable formulation (especially subcutaneous use) containing a GLP-1 receptor agonist (eg exenatide) and may be included with the DPP-4 inhibitor of the present invention has the following additive: tonicity adjustment Agents (eg, mannitol), antibacterial preservatives (eg, metacresol), buffers or pH adjusters (eg, glacial acetic acid and sodium acetate trihydrate in water for injection as a pH 4.5 buffer solution) It may further comprise solubilizers and / or stabilizers (such as surfactants or detergents).
In a further embodiment, the DPP-4 inhibitor according to the present invention is preferably administered by a transdermal delivery system. In another embodiment, a GLP-1 receptor agonist (particularly a short-acting GLP-1, GLP-1 mimetic or GLP-1 analog, such as exenatide or native GLP-1) is preferably Similarly, it is administered by a transdermal delivery system.

GLP-1 receptor agonists (especially short acting GLP-1, GLP-1 mimics or GLP-1 analogs, such as exenatide or native GLP-1) and / or DPP-4 inhibition of the invention Transdermal formulations (eg, for transdermal patches or gels) of drugs may be prepared according to known pharmaceutical techniques, for example using a suitable carrier and using additional additives. To facilitate percutaneous passage, for example, techniques involving the formation of microchannels or micropores in the skin, such as iontophoresis (based on low levels of current), sonophoresis (based on low frequency ultrasound) Alternatively, various methods and systems may be used, such as micropuncture, or the use of drug carrier agents (eg, elastic or lipid vesicles such as transfersomes) or permeation enhancers.
For further details regarding dosage forms, formulations and administration of the DPP-4 inhibitors of the invention and / or the GLP-1 receptor agonists of the invention, reference is made to the scientific literature and / or published patent documents, in particular herein. Are mentioned.

The pharmaceutical composition (or formulation) can be packaged in various ways. In general, an article for distribution includes one or more containers that contain one or more pharmaceutical compositions in a suitable form. Tablets are typically packaged in a suitable primary package for ease of handling, distribution and storage, and to ensure proper stability of the composition upon prolonged contact with the environment during storage. The The primary container for tablets can be a bottle or a blister pack.
For example, a suitable bottle for a pharmaceutical composition or combination (tablet) comprising a DPP-4 inhibitor according to embodiment A of the present invention is a glass or polymer (preferably polypropylene (PP) or high density polyethylene (HD-PE)) It can be made and sealed with a screw cap. The screw cap may include a child resistant safety closure (eg, a push-and-twist closure) to prevent or block access to the contents by children. If necessary (eg, in the high humidity region), the shelf life of the packaged composition can be extended by the additional use of a desiccant (eg, bentonite clay, molecular sieve or preferably silica gel).

  For example, a blister pack suitable for a pharmaceutical composition or combination (tablet) comprising a DPP-4 inhibitor according to embodiment A of the present invention comprises an upper foil (which can be broken by tablets) and a lower (containing a pocket for tablets) Or are formed from these. The upper foil has a metal foil coated with a heat-sealable polymer layer on the inner side (sealed side), particularly an aluminum or aluminum alloy foil (for example, 20 μm to 45 μm, preferably 20 μm to 25 μm thick). May be included). The lower part is laminated with a multilayer polymer foil (for example poly (vinyl chloride) (PVC) coated with poly (vinylidene chloride) (PVDC); or poly (chlorotrifluoroethylene) (PCTFE). PVC foils) or multilayer polymer-metal-polymer foils (such as cold-formable laminated PVC / aluminum / polyamide compositions).

To ensure a long shelf life, especially under hot and humid climatic conditions, additional overwraps or pouches made of multi-layer polymer-metal-polymer foils (eg laminated polyethylene / aluminum / polyester composition) are used in blister packs You can do it. Auxiliary desiccants in this pouch package (such as bentonite clay, molecular sieves or preferably silica gel) can further extend the shelf life under such severe conditions.
Injectable solutions may be available in typical suitable presentation forms that can be further packaged, such as vials, cartridges or prefilled (disposable) pens.
The article may further include a label or package insert that points to instructions customarily included in the commercial package of the therapeutic product, which includes indications, usage, dosage, administration, It may contain information about contraindications and / or warnings. In one embodiment, the label or package insert indicates that the composition can be used for any of the purposes described herein.

With respect to the first embodiment (Embodiment A), the typically required dosage of the DPP-4 inhibitor referred to in Embodiment A herein is that when administered intravenously: 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, and when administered orally, 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg 10 mg or 1 mg to 5 mg, in any case 1 to 4 times a day. Thus, for example, 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidine-1 The dose of -yl) -xanthine, when administered orally, is 0.5 mg to 10 mg per patient per day, preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.
For example, the dose of linagliptin when administered subcutaneously or intravenously to a human patient is in the range of 0.3 to 10 mg per patient, preferably in the range of 1 to 5 mg, especially 2.5 mg.

In further embodiments, for example, the dose of linagliptin is 0.1-30 mg per patient per day when administered subcutaneously to a human patient (eg, in an obese human patient or to treat obesity). Range, preferably in the range from 1 to 10 mg, in particular 5 mg.
A dosage form prepared with a pharmaceutical composition comprising a DPP-4 inhibitor referred to in Embodiment A herein contains 0.1-100 mg of the active material in a dosage range. Thus, for example, 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidine-1 Specific oral dosage contents of -yl) -xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

  With respect to the second embodiment (embodiment B), the dose of a DPP-4 inhibitor referred to in embodiment B of this specification to be administered to a mammal, eg, a human, eg, about 70 kg, is generally Per day per person may be from about 0.5 mg to about 350 mg, such as from about 10 mg to about 250 mg, preferably from 20 to 200 mg, more preferably from 20 to 100 mg of active part, or for example of the same size It may be from about 0.5 mg to about 20 mg, preferably 2.5 to 10 mg per person per day, preferably divided into 1 to 4 single doses. A single oral dosage content includes, for example, 10, 25, 40, 50, 75, 100, 150 and 200 mg of the active portion of a DPP-4 inhibitor.

  The oral dosage of sitagliptin, a DPP-4 inhibitor, is usually between 25 and 200 mg of the active moiety. The recommended dose of sitagliptin is 100 mg once a day calculated for the active moiety (free base anhydride). The unit dosages of sitagliptin free base anhydride (active moiety) are 25, 50, 75, 100, 150 and 200 mg. Specific unit dosages of sitagliptin (eg per tablet) are 25, 50 and 100 mg. Sitagliptin free base anhydride and an equivalent amount of sitagliptin phosphate monohydrate are used in the pharmaceutical composition, ie 32.13, 64.25, 96.38, 128.5, 192.75 and 257 mg, respectively. The For patients with renal failure, adjusted doses of 25 and 50 mg of sitagliptin are used. Typical dosages for the sitagliptin / metformin combination are 50/500 mg and 50/1000 mg.

  The oral dosage range of vildagliptin, a DPP-4 inhibitor, is usually between 10 and 150 mg per day, in particular between 25 and 150 mg per day, between 25 and 100 mg or between 25 and 50 mg or between 50 and 100 mg. Between. Specific examples of daily oral doses are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a more particular aspect, the daily dose of vildagliptin may be between 25 and 150 mg or between 50 and 100 mg. In another more particular aspect, the daily dose of vildagliptin may be 50 or 100 mg. The application of the active material can take place up to 3 times a day, preferably once or twice a day. A specific dosage is 50 mg or 100 mg vildagliptin. Typical dosages for the bildagliptin / metformin combination are 50/850 mg and 50/1000 mg.

  Alogliptin can be administered to a patient at an oral daily dose of between 5 mg / day and 250 mg / day, alogliptin can be administered between 10 mg and 200 mg, or between 10 mg and 150 mg, It may be administered between 10 mg and 100 mg (in each case based on the molecular weight of the free base form of alogliptin). Thus, specific oral dosages that can be used include, but are not limited to, 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg alogliptin per day. Alogliptin can be administered in its free base form or as a pharmaceutically acceptable salt.

  Saxagliptin may be administered to the patient at an oral daily dose of between 2.5 mg / day and 100 mg / day, and may be administered between 2.5 mg and 50 mg. Specific oral dosages that can be used include, but are not limited to, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg and 100 mg saxagliptin per day. Typical dosages of the saxagliptin / metformin combination are 2.5 / 500 mg and 2.5 / 1000 mg.

  Special embodiments of the DPP-4 inhibitors of the present invention are at low dose levels, for example, less than 100 mg or less per day per patient, preferably less than 50 mg, more preferably less than 30 mg per patient per day, or Orally administered a therapeutically effective DPP-4 inhibitor at an oral dose level of less than 20 mg, more preferably 1 mg to 10 mg, especially 1 mg to 5 mg (more particularly 5 mg) Divided into 1 to 4 single doses, which may be of the same size, in particular 1 or 2 single doses, preferentially orally administered once or twice daily (more preferentially Once daily), advantageously refers to those administered at any time of the day, with or without food, thus, for example, a daily oral dose of 5 mg BI 13 6 is a once-daily dosing regimen (ie 5 mg BI 1356 once a day) or twice a day dosing regimen (ie 2.5 mg BI 1356 twice a day) Regardless, it can be given at any time of the day.

GLP-1 receptor agonists (especially short acting GLP-1, GLP-1 mimics or GLP-1 analogs such as exenatide or native GLP-1) are typically administered by subcutaneous injection. For example, 1 to 30 μg, 1 to 20 μg or 5 to 10 μg, for example, once a day, twice or three times. The embodiments refer to those short-acting GLP-1 analogs (or generally any short-acting GLP-1 receptor agonist) to be administered at least twice daily, such as exenatide.
For example, exenatide is typically administered twice daily by subcutaneous injection (e.g. formulated as a bietta, for example at a dose of 5-30 μg, in particular 5-20 μg, preferably 5-10 μg, Dosage content is 5 or 10 μg).
While the dosage of active material in the combinations and compositions according to the invention can vary, the amount of active material must be such that a suitable dosage form is obtained. Thus, the selected dosage and selected dosage form will depend on the desired therapeutic effect, route of administration and duration of treatment. The dose range of the combination can be from the maximum tolerated dose for a single agent to a lower dose, for example up to 1/10 of the maximum tolerated dose.

A particularly preferred DPP-4 inhibitor to be emphasized within the meaning of the present invention is 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyne-1 -Yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine (also known as BI 1356 or linagliptin). BI 1356 exhibits a high titer, 24 hours duration of action and a wide therapeutic window. In type 2 diabetic patients receiving 1, 2.5, 5 or 10 mg of BI 1356 once or twice daily for 12 days, BI 1356 has a favorable pharmacodynamic and pharmacokinetic profile. Indicated (see, eg, Table 3 below), and achieving steady state rapidly (eg, reaching steady state plasma levels between days 2 and 5 of treatment in all dose groups (pre-dose on day 13) Preservation of long-lasting effects on DPP-4 inhibition (eg, 5 mg and 10 mg),> 90% of plasma concentration), minimal accumulation (eg, having an average accumulation ratio R A, AUC ≦ 1.4 at doses above 1 mg) Almost complete (> 90%) DPP-4 inhibition at dose levels of 92.3 and 97.3% at steady state, respectively, and over the 24 hour interval after drug intake With an inhibition of greater than 0%), and a significant reduction in blood glucose variability after 2 hours postprandial (above 1 day) at doses of 2.5 mg and above, and excreted in urine on day 1 The accumulated amount of unchanged parent compound is less than 1% of the administered dose and increases to about 3-6% or less on day 12 (renal clearance CLR , ss is relative to the administered oral dose) From about 14 to about 70 mL / min, eg, renal clearance is about 70 ml / min for a 5 mg dose) In people with type 2 diabetes, BI 1356 exhibits placebo-like safety and tolerability. As shown, at low doses of about 5 mg and above, BI 1356 acts as a true once-daily oral drug with a duration of DPP-4 inhibition of round 24 hours.At the therapeutic oral dose level, BI 1356 is Mainly liver Is excreted via the viscera, and only to a small extent (less than about 7% of the administered oral dose) is excreted via the kidney, BI 1356 is excreted unchanged, primarily via bile. The fraction excreted through the kidney increases only very slightly over time and with increasing dose, so that it is probably not necessary to change the dose of BI 1356 based on the patient's renal function. 1356 extrarenal excretion, combined with its low accumulation potential and wide safety margin, can be significantly beneficial in patient populations with a high prevalence of renal dysfunction and diabetic nephropathy.

  Quite often it is instructed to combine several different active ingredients with each other, since different metabolic dysfunctions often occur simultaneously. Thus, depending on the dysfunction diagnosed, a DPP-4 inhibitor may be combined with one or more active substances that may be conventional for each disorder, such as other anti-diabetic substances, particularly blood sugar levels or blood. One or more active substances selected from among active substances that lower intermediate lipid levels, increase blood HDL levels, lower blood pressure or indicated in the treatment of atherosclerosis or obesity, etc. When combined, improved treatment results can be obtained.

  In addition to their use in monotherapy, the DPP-4 inhibitors described above may be used in conjunction with other active substances, thereby obtaining improved therapeutic results. Such combination therapy may be given as a free combination of substances or in the form of a fixed combination, for example in the form of tablets or capsules. The pharmaceutical partner of the combination partner required for this can be obtained commercially as a pharmaceutical composition or can be formulated by a person skilled in the art using conventional methods. Active substances that can be obtained commercially as pharmaceutical compositions can be found in numerous places in the prior art, for example, the annual drug list, “Rote Liste” of the federal association of the pharmaceutical industry. Registered trademark) or in an annually updated compilation of manufacturer information on prescription drugs known as the "Physicians' Desk Reference".

  Examples of anti-diabetic combination partners are metformin; sulfonylureas such as glibenclamide, tolbutamide, glimepiride, glipizide, glyquidone, glibornuride and gliclazide; nateglinide; repaglinide; mitiglinide; thiazolidinediones such as rosiglitazone and pioglitazone; PPAR gamma modulators; PPAR-gamma agonists such as riboglitazone, mitoglitazone, INT-131 and valaglitazone; PPAR-gamma antagonists; Modulators; eg lobeglitazo PPAR-gamma / alpha / delta modulators such as; AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; GPR119 agonist (SMT3-receptor Pancreatic beta cell GCRP agonists such as -agonists), such as 5-ethyl-2- {4- [4- (4-tetrazol-1-yl-phenoxymethyl) -thiazol-2-yl] -piperidine, which is a GPR119 agonist 1-yl} -pyrimidine or 5- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-ylmethoxy] -2- (4-methanesulfonyl-phenyl) -Pyridine and the like; 11β-H SD-inhibitors; FGF19 agonists or analogs; alpha-glucosidase blockers such as acarbose, voglibose and miglitol; alpha2-antagonists; human insulin, insulin lispro, insulin gullysin, r-DNA-insulin aspart Insulin and insulin analogues such as NPH insulin, insulin detemir, insulin degludec, insulin tregopil, insulin zinc suspension and insulin glargine; gastric inhibitory peptides (GIP); amylin and amylin analogues ( GLP-1 and GLP-1 analogs such as exendin-4, such as exenatide, ex Senatide LAR, liraglutide, taspoglutide, lixisenatide (AVE-0010), LY-2428757 (PEGylated form of GLP-1), duraglutide (LY-2189265), semaglutide or arubyglutide; for example dapagliflozin, sergliflozin (KGT-1251), SGLT2-inhibitors such as atigliflozin, canagliflozin, ipragliflozin, luceogliflozin or tofogliflozin; inhibitors of protein tyrosine-phosphatases (eg Troduschemin); inhibitors of glucose-6-phosphatase; fructose-1, 6-bisphosphatase modulator; glycogen phosphorylase modulator; glucagon receptor antagonist; phosphoeno Rupyruvate carboxykinase (PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDK) inhibitors; inhibitors of tyrosine-kinases such as PDGF-receptor-kinase (50 mg to 600 mg) (European Patent Publication No. 564409, International No. 98/35958, US Pat. No. 5,093,330, WO 2004/005281 and WO 2006/041976) or serine / threonine kinase inhibitors; glucos containing glucokinase activators Kinase / regulated protein modulator; glycogen synthase kinase inhibitor; inhibitor of SH2-domain containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitor such as high dose salicylate; JNK1 inhibitor; protein Rasebegron, YM178, Sorabegron, Talibegron, N-5984, GRC-1087, Raffabegron, FMP825 and other beta 3 agonists; AS3201, zenarestat, fidarestat, epalrestat, lanirestat, NZ-314, CP- Aldose reductase inhibitors such as 744809 and CT-112; SGLT-1 or SGLT-2 inhibitors; KV1.3 channel inhibitors; eg [(3S) -6-({2 ', 6'-dimethyl-4'- GPR40 modulators such as [3- (methylsulfonyl) propoxy] biphenyl-3-yl} methoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid; SCD-1 inhibitors; CCR-2 antagonists; dopamine Receptor Gonists (bromocriptine mesylate [Cycloset]); 4- (3- (2,6-dimethylbenzyloxy) phenyl) -4-oxobutanoic acid; sirtuin stimulants; as well as other DPP IV inhibitors.

Metformin is usually about 100 mg to 500 mg or 200 mg to 850 mg (1 to 3 times a day) or about 300 mg to 1000 mg once or twice a day, or delayed release metformin is about 100 mg to 1000 mg or preferably 500 mg. A dosage of ˜1000 mg is given once or twice daily, or about 500 mg to 2000 mg once daily using various dosing regimens, varying from about 500 mg to 2000 mg per day, up to 2500 mg. Particular dosages can be 250, 500, 625, 750, 850 and 1000 mg metformin hydrochloride.
For children aged 10-16 years, the recommended starting dose of metformin is 500 mg given once a day. If this dose does not give sufficient results, the dose may be increased to 500 mg twice a day. Additional doses may be made, up to a maximum daily dose of 2000 mg, 500 mg per week, and may be given in divided doses (eg, 2 or 3 divided doses). Metformin can be administered with food to reduce nausea.

The dose of pioglitazone is usually about 1-10 mg, 15 mg, 30 mg or 45 mg once a day.
Rosiglitazone is usually given once a day (or divided into two doses) at doses of 4 to 8 mg (typical dosages are 2, 4 and 8 mg).
Glibenclamide (glyburide) is usually given once a day (or divided in two) at doses from 2.5 to 5 mg (typical dosages are 1.25, 2.5 and 5 mg) Or pulverized glibenclamide is given once (or divided in two) at doses from 0.75 to 3 to 12 mg (typical dosages are 1.5, 3, 4.5 and 6 mg).

  Glipizide is usually given once a day (or divided in 2 doses up to a maximum of 40 mg) at doses usually from 2.5 to 10-20 mg (typical dosages are 5 and 10 mg) or long-term Release glibenclamide is given once a day at doses of 5 to 10 mg (up to 20 mg) (typical dosages are 2.5, 5 and 10 mg).

Glimepiride is usually given once a day at doses of 1-2 to 4 mg (up to 8 mg) (typical dosages are 1, 2 and 4 mg).
The glibenclamide / metformin dual combination is usually given in doses from 1.25 / 250 once daily to 10/1000 mg twice daily (typical dosages are 1.25 / 250, 2. 5/500 and 5/500 mg).
The glipizide / metformin combination is usually given twice daily at doses from 2.5 / 250 to 10/1000 mg (typical dosages are 2.5 / 250, 2.5 / 500 and 5/500 mg).

The glimepiride / metformin two-drug combination is usually given twice daily at a dose of 1/250 to 4/1000 mg.
The rosiglitazone / glimepiride two-drug combination is usually given in doses from 4/1 mg once or twice daily to 4/2 mg twice daily (typical dosages are 4/1, 4 / 2, 4/4, 8/2 and 8/4 mg).
The pioglitazone / glimepiride dual combination is usually given once daily at doses from 30/2 to 30/4 mg (typical dosages are 30/4 and 45/4 mg).

The rosiglitazone / metformin combination is usually given twice daily at doses of 1/500 to 4/1000 mg (typical dosages are 1/500, 2/500, 4/500, 2 / 1000 and 4/1000 mg).
The pioglitazone / metformin combination is usually given in doses from 15/500 mg once or twice daily to 15/850 mg three times daily (typical dosages are 15/500 and 15/850 mg) Is).

The non-sulfonylurea insulin secretagogue nateglinide is given with meals, usually at doses of 60 to 120 mg (up to 360 mg / day, typical dosages are 60 and 120 mg); It is given with meals at doses from 5 to 4 mg (up to 16 mg / day, typical dosages are 0.5, 1 and 2 mg). The repaglinide / metformin two-drug combination is available in dosages of 1/500 and 2/850 mg.
Acarbose is usually given with meals at doses of 25 to 100 mg (usually 3 times a day). Miglitol is usually given with meals at doses of 25 to 100 mg (usually 3 times a day). Voglibose is usually given with meals at doses of 0.2 to 0.3 mg (usually 3 times a day).

  Examples of combination partners that lower blood lipid levels are HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; bezafibrate, fenofibrate, clofibrate, genfibrozil Fibrates such as etifibrate and ethofylcrofibrate; nicotinic acid and its derivatives such as acipimox; PPAR-alpha agonists; for example {4-[(R) -2-ethoxy-3- (4-trifluoro PPAR-delta agonists such as methyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic acid; inhibitors of acyl-coenzyme A: cholesterol acyl tigers such as avasimibe Spherase (ACAT; EC 2.3.1.26); cholesterol absorption inhibitors such as ezetimibe; substances that bind to bile acids such as cholestyramine, colestipol and colesevelam; inhibitors of bile acid transport; D4F, reverse D4F, LXR regulation HDL-modulating active substances such as active substances and FXR-modulating active substances; CETP inhibitors such as torcetrapib, JTT-705 (Darcetrapib) or compound 12 (anacetrapib) from WO 2007/005572; LDL receptor modulators; MTP inhibition Drug (romitapide); as well as ApoB100 antisense RNA.

The dose of atorvastatin is usually 1 mg to 40 mg or 10 mg to 80 mg once a day.
Examples of combination partners that lower blood pressure are beta-blockers such as atenolol, bisoprolol, seriprolol, metoprolol and carvedilol; Drugs; calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, rasidipine, lercanidipine, manidipine, isradipine, nilvadipine, verapamil, galopamil and diltiazem; ramipril, lisinopril, cilazapril, priapril Perindopril, fosinopril and trandolap It is a well telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, an angiotensin II receptor blockers such azilsartan and eprosartan (ARB); Le ACE inhibitors such as.
The dosage of telmisartan is usually 20 mg to 320 mg or 40 mg to 160 mg per day.
Examples of combination partners that increase blood HDL levels are: cholesteryl ester transfer protein (CETP) inhibitors; endothelial lipase inhibitors; ABC1 modulators; LXRalpha antagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha / beta Modulators; and substances that increase the expression and / or plasma concentration of apolipoprotein AI.

  Examples of combination partners for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); alizyme (cetiristat); dexfenfluramine; axoquin; cannabinoid receptor 1 antagonists such as rmonabant, a CB1 antagonist; MCH-1 receptor MC4 receptor agonists; NPY5 and NPY2 antagonists (eg, Berneperit); beta 3-AR agonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such as APD356 (lorcaserine); myostatin inhibitors; Acrp30 and Adiponectin; steroyl CoA desaturase (SCD1) inhibitor; fatty acid synthase (FAS) inhibitor; CCK receptor agonist; ghrelin receptor Modulator; PYY3-36; orexin receptor antagonists; and Tesofenshin; and bupropion / naltrexone combination of two agents, bupropion / zonisamide, topiramate / phentermine and pramlintide / metreleptin.

Examples of combination partners for the treatment of atherosclerosis are phospholipase A2 inhibitors; inhibitors of tyrosine-kinases such as PDGF-receptor-kinase (50 mg to 600 mg) (European Patent Application Publication No. 564409, International Published 98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281 and WO 2006/041976); oxidized LDL antibody and oxidized LDL vaccine; apoA-1 Milano; ASA; As well as VCAM-1 inhibitors.
The present invention is not to be limited in scope by the specific embodiments described herein. Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from this disclosure. Such modifications are intended to fall within the scope of the appended claims.
All patent applications cited herein are hereby incorporated by reference in their entirety.

  Further embodiments, features and advantages of the present invention may become apparent from the following examples. The following examples serve to illustrate, by way of example, the principles of the invention without limiting the invention.

Linagliptin, which may be used in combination with a GLP-1 receptor agonist, reduces body weight and body fat mass and changes in taste preferences Obesity model Male Sprague Dawley rats are from Taconic at 6 weeks of age. Throughout the study, rats are two diets—a standard rodent diet, Altromin 1324 (Brogaarden, Denmark), a chocolate spread (Nutella, Ferrero Italy), peanut butter, and a standard rodent diet. A high fat paste (HFD) made from powder of Altromin 1324 (Brogaarden, Denmark) can be freely selected. Animals are kept on that diet for 23 weeks prior to the experiment. Each rat was singly one week prior to the first dose (week 28).
Day 0 is the first dosing day. Animals were treated twice daily (subcutaneous saline, linagliptin 0.5 mg / kg, natural GLP-1 0.4 mg / ml and combinations thereof), between 7 am and 9 am and 3 pm Administration was received between ~ 5 o'clock. The animals were dosed for 32 days. Rats were sacrificed on study day 33.

Major Findings Subcutaneous injection treatment with linagliptin and natural GLP-1 twice daily results in significant body weight (BW) loss of up to 8%. Data show the mean value of 10 animals + SEM (standard error of the mean) (FIG. 1).

Thus, body fat mass was significantly reduced after application of the combination of linagliptin and natural GLP-1 (FIG. 2).
Animals treated with linagliptin / GLP-1 have a change in food preferences in a) reduced intake of high fat diet, and b) change to standard diet (FIGS. 3a, 3b).

Co-administration of the DPP-4 inhibitor linagliptin and natural GLP-1 induces weight loss and appetite suppression Linagliptin is a dipeptidyl peptidase (DPP) -4 inhibitor approved for the treatment of type 2 diabetes. DPP-4 inhibitors are neutral to body weight, suggesting that increased endogenous incretin levels may not be sufficient to promote weight loss itself. Here, the effect of subcutaneous co-administration of linagliptin and natural GLP-1 (7-36) is evaluated in a rat model. In normal body weight rats, short-term linagliptin treatment (0.5 mg / kg subcutaneously injected twice daily) has no effect on nocturnal food intake, whereas GLP-1 treatment (0. Subcutaneous injection of 4 mg / kg twice daily causes a slight and short suppression of food intake. In contrast, co-administration of linagliptin and GLP-1 induces an active and rapid appetite suppressive response. In diet-induced obese (DIO) rats, 14-day monotherapy with linagliptin or GLP-1 does not affect body weight, but an additional 14-day linagliptin (0.5 mg / kg subcutaneously twice daily) ) And GLP-1 (0.4 mg / kg subcutaneously twice a day) continues the continuous decrease in food intake and body weight (−6.4 ± compared to baseline body weight). 0.8%). Interestingly, the weight loss effect of the combination of linagliptin and GLP-1 treatment is associated with a marked increase in preference for a standard diet over intake of a palatable high fat-high carbohydrate diet. In addition, combination therapy with linagliptin and GLP-1 specifically increases preprodynorphin mRA levels in the nucleus accumbens. These data demonstrate that combination treatment with linagliptin and GLP-1 synergistically decreases body weight in an obese rat model. This anti-obesity effect is caused by appetite suppression and changes in food preferences that appear to be associated with increased dynorphin activity in dopaminergic forebrain regions involved in reward prediction and habit learning. In conclusion, co-administration of linagliptin and GLP-1 (natural GLP-1, GLP-1 receptor agonists, or GLP-1 mimetics or analogs such as short-acting GLP-1) can thus result in weight management and diabetes Combinations with management, and appetite suppression, changes in food preferences, and weight loss in obese patients may be promising as novel therapeutic principles.

Glucose and body weight control with a combination of linagliptin and voglibose Investigating whether linagliptin, a dipeptidyl peptidase-4 inhibitor, and alpha-glucosidase inhibitor (AGI) voglibose can improve or maintain blood glucose and body weight control . Male ZDF-Leprfa / Crl (diabetic fa / fa) rats fed on a standard diet are assigned based on body weight and fasting plasma glucose (FPG) (n = 10 / group). In two trials-S1: vehicle, linagliptin (1 mg / kg), high dose voglibose (10 mg / kg), or linagliptin + voglibose; S2: same as S1 except low dose voglibose (1 mg / kg)- Rats are administered orally daily for 4 days. An oral glucose tolerance test (4 g / kg, oral administration) is performed on day 4 and body weight is recorded daily. The average FPG values on day 4 are 7.39 mM and 8.18 mM in S1 and S2, respectively, and the average insulin values are 2.01 ng / mL and 3.76 ng / mL. Compared to vehicle for improved glucose control, linagliptin (S1-10%, S2-17%; both P <0.05), voglibose (S1-33%, P <0.001; S2-18%, P <0.01), linagliptin + voglibose (S1-33%, S2-33%; both P <0.001). The improvement in glucose control is enhanced by linagliptin + low dose voglibose compared to each single drug (P <0.01). After 5 minutes of sucrose challenge, plasma active GLP-1 was compared to vehicle with linagliptin (S1 160%, P <0.01; S2 144%, P <0.001) and linagliptin plus voglibose (S1 834%). S2 639%; both increase at P <0.001), which is greater than linagliptin or voglibose alone (all P <0.001). Compared to vehicle, linagliptin-induced improvement in glucose control is independent of changes in overall body weight (S1 + 0.7%, S2-0.2%; both P = ns). In contrast, voglibose (S1-3.0%; S2-1.7%) and linagliptin + voglibose (S1-3.4%; S2-2.0%) were compared to vehicle for overall (All P <0.001). Linagliptin + voglibose therapy enhances improved glucose control. This combination can minimize the side effects of AGI. This is because low doses of voglibose may be needed to maintain glycemic control and may have additional beneficial effects through synergism of elevated active GLP-1 levels.

Claims (15)

  1. May be used in combination with one or more drugs in a patient in need thereof,
    A combination of a DPP-4 inhibitor, preferably linagliptin, and an α-glucosidase inhibitor as selected from voglibose, miglitol and acarbose,
    Treating and / or preventing metabolic diseases, especially diabetes, especially type 2 diabetes, and / or improving weight control, reducing weight, inducing satiety, suppressing gastric emptying, Or reduce food intake and / or prevent, protect from, reduce the likelihood or occurrence of side effects associated with α-glucosidase inhibitors, or minimize side effects associated with α-glucosidase inhibitors Combination for use in one or more of limiting.
  2.   The combination for use according to claim 1, wherein the side effects associated with the α-glucosidase inhibitor are selected from dyspepsia, hunger or diarrhea, or gastrointestinal adverse effects such as nausea or vomiting.
  3.   3. Combination for use according to claim 1 or 2, wherein the patient is a diabetic patient who may have or may be at risk for microvascular and / or macrovascular disease or complications.
  4.   The patient is obese or overweight, or at risk thereof, and / or has or is at risk for renal dysfunction (eg, of mild, moderate, severe or ESRD stage), and / or Or a combination for use according to claim 1, 2 or 3, wherein the patient is a type 2 diabetic patient with a reduced dose of an α-glucosidase inhibitor.
  5.   The combination for use according to claim 1, 2, 3 or 4, wherein the patient is a type 2 diabetic patient who is obese or overweight.
  6.   6. Combination for use according to any one of claims 1 to 5, wherein the patient is a type 2 diabetic patient in need of a dose reduction of an [alpha] -glucosidase inhibitor.
  7.   7. A patient according to any one of claims 1 to 6, wherein the patient is a type 2 diabetic patient with insufficient glycemic control despite diet and / or exercise alone (as first line therapy). Combination for use.
  8.   The patient is a type 2 diabetic patient with insufficient glycemic control despite monotherapy (as a second-line therapy) with an alpha-glucosidase inhibitor in addition to diet and / or exercise. A combination for use according to any one of 1 to 6.
  9.   A combination of an α-glucosidase inhibitor and one or more other anti-diabetic drugs, such as metformin, sulfonylurea, or insulin, in addition to diet and / or exercise (as a third line therapy) The combination for use according to any one of claims 1 to 6, wherein the combination is a type 2 diabetic patient with insufficient glycemic control.
  10.   10. Combination for use according to any one of claims 1 to 9, wherein an alpha-glucosidase inhibitor is present or is used at low doses and / or low frequent doses.
  11.   When the α-glucosidase inhibitor is co-administered with a DPP-4 inhibitor, preferably linagliptin, preferably at low doses such as 0.2-0.3 mg once, twice or three times daily. 11. Combination for use according to any one of claims 1 to 10, which is voglibose.
  12.   When the alpha-glucosidase inhibitor is co-administered with a DPP-4 inhibitor, preferably linagliptin, preferably as low as 25-50 mg (or up to 100 mg) once, twice or three times daily 11. Combination for use according to any one of claims 1 to 10, which is a dose of acarbose.
  13.   When the α-glucosidase inhibitor is co-administered with a DPP-4 inhibitor, preferably linagliptin, preferably a low dose such as once, twice or three times 25-50 mg (or up to 100 mg) 11. A combination for use according to any one of claims 1 to 10, which is miglitol.
  14.   14. Combination for use according to any one of claims 1 to 13, wherein the DPP-4 inhibitor and the alpha-glucosidase inhibitor are administered to the patient simultaneously, sequentially or separately.
  15.   The DPP-4 inhibitor is 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino 15. Combination for use according to any one of claims 1 to 14, which is -piperidin-1-yl) -xanthine, or a pharmaceutically acceptable salt thereof.
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